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7.88 Lecture Notes - 77.24/7.88J/5.48JThe Protein Folding ProblemTropomyosin and S-peptide• Sequence determinants of Coiled Coil Structure• Tropomyosin• Circular Dichroism• Tropomyosin thermal denaturation/renaturation• Chain Recognition, Association, RegistrationA. Revisit Sequence determination of Coiled CoilsH – X – X -H – P – X - P – H – X – X – H – P – X - P- H – X – X - H-P – X -PLets draw as helical wheel:Note side chain interactions above and below plain:Now lets flip the sequence 18:Sequence:• 1,4 residues: hydrophobic core• 5,7: selectivity, polarity• 2,3, 6: Quaternary interactions; cellular functionsPerhaps: But for TM and other coiled coils, easy to see that they encode:Lets review muscle structure:Theta in degrees;Light waves are transverse vibrations; can be vibrating in various planesperpendicular to direction of propagation.B. TropomyosinIN vitro unfolding/refolding of a coiled-coil: Tropomyosin:Properties of TropomyosinDenaturation/Renaturation of TMReversibilityCoupling of secondary and tertiary structureFrom thermal denaturation curve: Conformation = f (sequence + environment)Possible pathwaysQuestion: Is this conformation/subunit organization encoded by amino acidsequence; perhaps protein folds in association with other components of muscle structure?However, for these structures, only fiber diffraction; no 3-D crystals, no high res structure; not in PDB. In fact in first edition of Branden and Tooze no mention of coiled coils, because not present among globular soluble proteins!!Why tropomyosin: Given that alpha helices are critical conformation of keratinpolypeptide chains:What about examining keratin folding into keratin helices using the in vitromethodology of Anfinsen???Not possible: severe limitations in these systems;Mature fibrils highly covalently crosslinkedSolubilization requires severe treatment and does not yield homogenous population of protein chains.Only just recently has it been possible to obtain the precursor forms of keratin chains prior to folding and assembly into hair - from tissue culture and from products of cloned genes:Tropomysoin function and organization:Remind you of structure of striated muscle:• Thin filaments from M band• Thick filaments which are bipolar:Tropomyosin Structure:• rodlike, 2nm x 41 nm when observed in the electron microscope as soluble molecules.• molecular weight 65.5 kd.• two chains of 284 residues, a and b, with slight differences in sequence (39 residues)• Almost 100% alpha helical and consists of two alpha helical chains wrapping around each other.• Linear: No turns• Relatively high concentration of charged amino acids, but unusually stable to changes in Ph on both acid and alkaline sides, indicating that electrostaticinteractions not important for maintenance of alpha helical coiled coil structure • Interact with actin filaments to form long filamentous structures that lie in each of the two long period grooves on opposite sides of thin filaments in muscle.• pack head to tail with an 8-9 residue overlap• Bind Troponin Subunit - Troponin the other regulatory protein in the thin filaments is bound to each tropomyosin molecule.• Actin : tropomysoin : troponin present in 7:1:1 stoichiometry.Its function is control rod restricting axis of myosin head groups to actin filament;moving back and forth during muscle contraction cycle; regulated by calciumPurified Tropomyosin has never been observed to form three D crystals; So nocrystal structure; (not even in Index of Branden and Tooze) However forms 2-D open crystal nets;Original structural data came from X-ray scattering and electron microscopy ofunusual two dimensional crystalline form; kite-likeC. Circular dichroismLight represents transverse vibration; can be polarized, restricted to certain planes;A plane polarized beam is one in which electric vector vibrates in just a singledirection in plane perpendicular to propagationPlane of polarization can rotate, so circularly polarized, either clockwise or not, left or right; polaroids have crystallites which absorb one component not opposite; formed under stress so that crystallites are aligned;Chiral L amino acids differentially absorb light with beams of left and right circularly polarized vectors; two components therefore travel at different speeds throughpolypeptides and proteins, which results in rotation of the plane of polarizationDifferential absorption of left and right circularly polarized light;• Far UV signal (200-230)- Monitors backbone conformation peptide bond itself, • near UV - ring absorption at longer wavelength –Function of wavelength; so scan ellipticity versus wavelengthAnalogous to absorption spectra; scan versus wavelengthExpressed as theta, Molar ellipiticity, measure differences between left and right polarized light compared to input light.For helical proteins, net negative, so more negative, more helical:Best for alpha helix because of a double dip ; Distinguishes alpha helices, betasheets and random coils reasonable well.D. Denaturation and Renaturation of TropomyosinFirst: Consider thermal-denaturation for proteins you are familiar with:• Egg white: lysozyme plus ovalbumen?• Milk: Casein + alphal lactalbumen?• Collagen (gelatin) ?• Gluten?• ActinOutcome of thermal denaturation processes depend on protein itself, not generally feature of polypeptide chains;Now lets consider the folding and association of purified tropomyosin chains:Does tropomyosin refold from the denatured state?? That is, does tropomyosinamino acid sequence by itself determine coiled-coil conformation??Equilibrium Denaturation: All measurements after process has come to equilibrium or steady state; often confused in the literature, but I will be presenting trueequilibrium data.These are to be distinguished from kinetic analysis; reaction as a function of time.This was RNase data.Tropomyosin exhibits distinct melting transition when heated:Lori L. Isom, Marilyn Emerson Holtzer and Alfred Holtzer (1984) alpha-helix to Random-Coil Transition of Two-Chain, Coiled Coils. Experiments on the Thermal Denaturation of alpha-Tropomyosin and beta-Tropomyosin Macromolecules, 17 2445-2447.Purified reduced tropomyosin:Rabbit cardiac muscle:• Two chains alpha and beta;• differ by 39 residues,• 11 of which are at hydrophobic positions:Each point sits 10 minutes, fully reversible; true equilibrium;Draw test-tubes: change water bath:Or multiple samples put in different water baths:Tm is around 50ºC.What is state of polypeptide chain??Certainly not alpha helix: but amino acid sequence remains the same; but we said sequence determines fold!!??Fold = f (Sequence ; environment)However, when cool (draw dashed line); identical curve:It is possible to determine the molecular weight of the molecules in these samples by a number of techniques:• Light scattering• Sedimentation velocity• Sedimentation equilibriumDetermine molecular weight above Tm= equals 1/2 of starting MW.This material is half the molecular weight of starting material!!So it is monomeric.What is its conformation: not alpha helical, “disordered, random”Thus alpha helicity is coupled to dimerization, and vice versa, loss of alpha helicity is coupled to dissociation.What is Pathway for Coiled Coil Formation??What would you predict as the physical state under these conditions?So What are steps in reaction?How could you test model?Is there evidence for gain of alpha helicity prior to increase in molecular weight?? No.Concentration dependence: Might depend on square of concentration? Diluted by two; No change??In fact dilute by 1,000 - not easy detect: Questionable:More direct route: Use light scattering to follow size of molecule:Data: L Number of chains versus temperature for reduced or block chains, to prevent air oxidation cross linking.Light scattering curve follows CD curve exactly:Denaturation and dissociation tightly coupled:NB: These alpha helical amino acid sequences are not alpha helices when free in solution:secondary structure is function of tertiary structure (!?): Important to avoid intellectual error of thinking that conformation is simplef(sequence);always f(sequence/environment)So:• Registration information built into amino acid sequence:• What would one predict about helicity;• Pathway: Form helices then associate:• What prediction: helicity versus temperature??• Pathway: No helix until associate: Stability should be f(concentration)• Yes: But very hard to detect;• We will come back to thisIn fact tropomyosin molecules pack parallel, in register.Could these helices associate if in register??So not just Folding, Association, but also Registration!Could there be out of register intermediates??1....14. (284)1.....14. (284)Tropomyosins differ in different muscle, for example between Striated skeletalmuscle, and smooth cardiac muscle; variation is generated by differential splicing at messenger RNA level: 13 exonsNote that lots of sequence available to do other stuff:What is Role of Remaining Sites in Sequence??Residues "b,c and f" lie on the outermost surface of the coiled coil molecule andprobably have a special role in the aggregation of the coiled coil molecule into alarger assembly and in the function of the molecules.In muscle this is clear: these sites are involved in interaction with actin monomers in actin filament!Conclusion: Folding information dispersed through Amino Acid Sequence!!In order to understand rules, need to know which amino acids carry the information for conformation.If heptad repeat determines coiled coil structure, and any heptad repeat can formcoiled coil, how do they find their correct partners?Recognition/ specificity in chain association; But since association not uncoupledform folding, can’t uncouple folding from recognition.In the 1980s there were significant advances in the design and construction ofspectrometers that could measure circular dichroism, and also a more sophisticated appreciation of the coiled coil structure:To give you a sense of this aspect of problem, let me describe more recent studies on tropomyson, and how alpha recognizes beta chain: A very penetrating study was carried out by Sherwood Lehrere and colleagues at the Boston Biomedical Research Institute: They were interested in the question initially of whether in muscle there weredifferent populations of tropomysins: playing different regulatory roles; skeletalmuscle versus cardiac muscle• Alpha/alpha• Beta/beta• Or alpha beta:It became clear that in the muscle major species was alpha/beta; That raised thequestion of how alpha and beta chains select heteropartner over homopartner: Sherwin S. Lehrer, Yude Qian and Soren Hvidt (1989)“Assembly of the Native Heterdoimer of Rana esculenta Tropomysoin by Chain Exchange” Science, 246, 926-928.Lehrer’s experiments were done with TM from Frog RanaEquilibrium unfolding: Incubate sample at temperature for set amount of time; record spectra; express as % helix:Curve for alpha/alpha: 50ºCCurve for beta/beta = 36ºCCurve for alpha beta; looked like two populations: but physical characterizationindicated one.How think about midpoints: could be two stable populations; but very rare:Aha: Not a single transition; two transitions; one at lower temperature 36º second sharper one at higher temperature, midpoint 50ºC.Possibilities:• Heterogeneity in sample: TM is a mixture of two species:• Homogenous sample: Two different domains, one high tm, other low tm On cooling, observed higher temperature transition, but lost lower temperaturetransition, and didn’t regain same level of helicity as wild type:Perhaps one domain refolds, other doesn’t; or one species refolds, or other doesn’t Proceeded to purify by ion exchange chromotography (different salts) alpha chains and beta chains.Under physiological conditions alpha/alpha dimmers, β/β dimers:Carry out melting:• Alha/alpha shows single transition with midpoint about 50ºC• β/β shows transition at much lower temperature: around 30ºC Both indicate that dissociation of dimer is coupled to loss of alpha helicity:The unfolding of the refolded material; curve fit perfectly by sum of alpha/alpha and beta/betaUnder these conditions; two chains fold back to homo dimers; melting curve is of mixture:The first transition of native TM alp[ha/beta must be an exchange reaction of the form2alpha/beta >> alpha/alpha + 2 βsince losing helicity; but still have a species present that shows cooperativetransition identical to alpha/alphaUnder conditions where native structure being destabilized; fast equilibrium between[Native}2 , > ?[I]n < > 2 [U]2No species long lived enough to directly characterize:Lets examine the rate of this process: takes about 50-100 seconds to cool from 60ºC to 34ºC;Helicity regained rapidily:Now continue to incubate for another 5,000 seconds about 8 hours:Helicity and thermostability returnsE. Chain Recognition, Association, RegistrationRecognition process; initiation of helicity > registration> propogation>Careful investigation of Chain Recognition:Erin O’shea, Rheba Rutkowski, Walter F. Stafford III, Peter S. Kim (1989)Preferential Heterodimer Formation by Isolated Leucine Zippers from Fos and Jun Science, 245, 646-648.DNA binding proteins Fos and Jun each contain leucine zipper regions with five leucines at every seventh residues. Partial homology to GCN$.Synthesized peptides with cysteines and two glycines as spacers at N-terminus.Run on HPLC;Reduced, two single peaks of each peptide;Oxidized, single peak;So no fos/fos or jun/jun at eqilibirum under these condtions;Control: denature in GuHCL, oxidize, now recover all three speciesPrepare all three dimers, examine by circular dichroisims:All three very helical:What happens if mix together homodimers;In absence of oxidizing agent:In presence of oxidizing agent - Only heterodimer!So exchanging below melting transition;Examine stability:• Fos/jun Tm around 54• Jun/Jun around 53• Fos/fos 37C.Fos is +4 net charge:Jun is –4 net charge;So electrostatic stabilization from heterodimerElectrostatic repulsion in homodimers;Classes of helices:• Fibrous proteins – Insoluble, helicity deduced• In globular proteins, observed by X-ray diffraction –ridges into grooves packing• In coiled/coils, X-ray scattering and diffraction – is this packing ridges into groves??• isolated??Coiled Coils stabilized by:• Hydrophobic strip• Charge charge interactions/salt bridges• H- bonds• buried hydrophobic coreToday we will focus on the formation of an alpha helix within a non helical polypeptide chain and the sequence specific interactions which stabilize and destabilize such species.。

麻省理工MIT(微观经济学)lec01_02_orderings and utility representation

14.123 Lectures 1-2, Page 3
Introduction
• Economics is about explaining and predicting choice. • It is assumed that economic agents choose their most desirable alternative among the set of feasible ones. – Interpret it “as if”, not necessarily “deliberate”. – “This morning I took the shuttle to MIT because this was the best possible way to come in.” Discuss. • Desirability is represented by preferences and/or utility. – Attitudes may be expressed over outcomes never experienced (Would you prefer to be Superman or Spiderman?).
14.123 Lectures 1-2, Page 6
Utility Representation
• DEF. Utility fcn u : X → represents if u(x) ≥ u(y) x y. • THM: If u represents , then is complete and transitive. ■ Follows from the same properties of ≥ on real numbers. ■ • THM: If X is finite and is complete and transitive, then there exists a utility function that represents . ■ u(x) = |{y∈X : xy}|: # of alternatives that x beats weakly.■ • THM: If X is countable and is complete and transitive, then there is a utility function with a bounded range that represents . ■ X ≡ {x1,x2,…}. Let u(x-1)=0, u(x0)=1. For all n=1,2,…, set u(xn) = [max{u(xk)|xnxk,n>k} + min{u(xk)|xkxn,n>k}]/2 .■

MIT-SCIENCE-Lectures-lec7_xu

Qi ⎧ ⎫ ˆ K (0) = P ⎪ X w + 1[ Ln > 0] ≤ s , ∀i ∈ K ⎪ ≤ f K ( w) ˆ f ⎨ i ∑ i ⎬ i n =0 ⎪ ⎪ ⎩ ⎭
K
ˆ Li to Li = [ Li − w]+
•
Knowing demand in advance (by w time units) is more effective, in terms of order fill rate, than reducing the supply leadtime of components.
7/6/2004
Ping Xu
2
Model
• • • M different components, and F = {1,2,…,m} are the component indices. Customer orders arrive as a stationary Poisson process, {A(t), t>=0}, with rate λ . Order type K: it contains positive units of component in K and 0 units in F\K.
– – –
K An order is of type K with probability qk, ∑ K q = 1 K K Type K order stream forms a compound Poisson process with rate λ = q λ K K A type-K order has Q j units for each component j, QK = (Q j , j ∈ K ) has a known discrete distribution.

MIT-SCIENCE-Lectures-lec12(1)

12. FILM SHOWING & DISCUSSION: "BLACK ROBE" (3/16/04)(continued)Very sincere, earnest film. Used Indian actors. Tried not to idealize or mythologize, but still angered Native Americans, including actors in film.Line from histories through novel to film. Bryan Moore, novelist, read essay by Graham Green, went to history by Francis Parkman, who was quite anti-Indian and anti-Iroquois. Then to the Relations. Wrote novel. Bruce Beresford, Australian director, made into film. Toned down in places, but still very harsh.What can you see in film that comes from the Relations? "These are our fathers." Admonition about how will have to stay up with Indians etc. Father Laforgue patterned on specific Jesuit. Smokey hut, other difficult conditions. Sorcerer enemies, even specific dwarf sorcerer, his name (though comes from another enemy of Jesuits, not the dwarf). Long journey westward (which film drastically simplifies). Capture by Iroquois, even detail of priest coming out of hiding. Torture of priest. Politics of baptism.How does the film depart from the Relations? In character of priest? In what way is Father Laforgue more a character from the 20th century?---doubts, willingness at end to accept Indian viewpoint. What about the attitudes towards Baptism of the dying priest at the end of the film?---not characteristic of Jesuits, no mass Baptism. What is Father Laforgue's great revelation?--this worldly orientation.How is the representation of language a problem in films about Indians?--or about any other foreigners? Cf. Mel Gibson film on Jesus. Indians mostly had to learn new language, memorize lines. It shows: very slow, halting. How does this affect image of Indians---stolid, impassive, not big talkers. What would the alternatives be?What Indian groups does the film distinguish? How does it differentiate/contrast them? Montagnais (Innu), represent the most uncomprehending, most unused to French, express most naive reactions, first contact. Actually had been in contact the longest. Iroquois, villains, the ferocious other. How conveyed? Village like Star Wars or a Kurosawa castle. Most ferocious face paint. Wanton cruelty. Gloating. Not surprising that real Iroquois upset.Huron and Algonkian, in middle. At different points, each group as everyman or every-Indian.How does the film represent Indians in general? Fierce but realistic. At one with world, which fierce, bleak place.How does the film represent the clash of religions? What epitomizes each religious outlook: dreams versus heaven. What is wrong with focusing on heaven? Defers everything, diverts from real life. How does emphasis on heaven depart from relations? Which side looks better/more realistic in film?What can you say about the depiction of violence and sexuality in the film and their meaning? What do you think about Churchill’s criticism? Do you think the filmmakers really think the sexuality of the Indians and Daniel is worse than Laforgue’s? Whose sexuality is being criticized?Do you think the film lets us understand the killing and the torture in their cultural context? (See the readings by Wallace and Richter.) What about Churchill’s critique as a whole?Larger significance of violence, savagery, a summing up whole encounter. The big thing that must be explained, 500 pound gorilla. Traditional blaming of Indians, more recently Whites.What is the significance of the landscape?If the film can be about other things as well as 17th century France, what are those other things? Whose sexuality do you think it has in mind? What country besides France and Canada?---Ireland. How do you guess it might relate to Moore's life, his situation? his relationship to church? His place in world?In what ways is "Black Robe" the answer to or antithesis of "Dancing with Wolves"?---anti-romantic, anti-idealization of Indians. Dunbar (and many others, .e.g Hawkeye) taken in by Indians or absorbs essence/virtues of Indians, more Indian than the Indians. Laforgue learns lesson, but Indians still radically the other, will never be absorbed. Detached from his own past but not absorbed in new reality. Alone in world.。

MIT14_15JF09_lec09

In all of these cases, interactions with other agents you are connected to aﬀect your payoﬀ, well-being, utility. How to make decisions in such situations? → “multiagent decision theory” or game theory.
Reading: Osborne, Chapters 1-2. EK, Chapter 6.
2
Networks: Lecture 9
Introduction
Motivation
In the context of social networks, or even communication networks, agents make a variety of choices. For example:
3
Networks: Lectu“Rational Decision-Making”
Powerful working hypothesis in economics: individuals act rationally in the sense of choosing the option that gives them higher “payoﬀ”.
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u (c ) dF a (c ) ≥ U (b ) =
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u (c ) dF b (c ) .
7
Networks: Lecture 9
Introduction
From Single Person to Multiperson Decision Problems

MIT-SCIENCE-Lectures-lec17_handout

Massachusetts Institute of TechnologyOrganic Chemistry 5.13October 20, 2003Prof. Timothy F. JamisonNotes for Lecture #17Sigmatropic RearrangmentsWood ward-Hoffmann Rules for Sigmatropic RearrangmentsStereochemical Course# Electrons Thermal Mode Photochemical Mod e 4n + 2 [s,s] [s,a]4n [s,a] [s,s]Continued on next page...Summary of Unit 3Molecular Orbital Theory, Pericyclic ReactionsA. Molecular Orbital Theory1. Ethylene2. Allyl cation, radical, anion3. 1,3-Butadiene4. Benzene5. Cyclobutadiene – Frost’s Circle (Polygon Rule)B. Cycload d ition Reactions1. Diels-Alder Reactiona. Basics – diene + dienophile (electron-poor)b. Only s-cis conformation of diene reacts.c. Cantharidin exampled. Stereochemical course – part 1: Always suprafacial with respect todienophile – stereospecific.e. Diels-Alder is a concerted reactionf. Frontier Molecular Orbital analysis of Diels-Alder reaction. H OMO of dieneinteracts with LUMO of dienophile. “HOMO/LUMO analysis”.g. Stereochemical course – part 2: Always suprafacial with respect to diene.Disrotatory motion of orbitals.h. Woodward-Hoffman rules correctly predict the stereochemical course of theDiels-Alder reaction (and all other cycloaddition reactions): π4s + π2s.i. Regioselectivity – “ortho-para rule”. Not governed by W-H rules, but ageneral trend.j. Diastereoselectivity – Alder endo rule.k. MO explanations: Coefficients of wavefunctions that represent orbitals vary with substitution. Secondary orbital interactions between dienophile andcarbon(s) 2 and/or 3 of diene favor endo approach of dienophile.2. Photochemical [2+2] Cycloadditiona. Review of 4 requirements of cycloaddition (concerted, pericyclic; cyclic T.S.; 2separate arrays of orbitals; form 2 sigma bonds) and what W-H predicts forphoto [2+2] (π2s + π2s)b. Explanation – HOMO/LUMO analysis. Excite electron to higher energyorbital, which becomes HOMO.c. Examples: cis-2-butene + maleic anhydride, thymidine dimmers3. Thermal [2+2] Cycloaddition – Ketenes + Alkenesa. MO analysis and W-H rules predict π2s + π2ab. Side-on approach of diene and ketene (“+” sign)4. Dipolar [4+2] Cycloaddition, Thermala. Diene vs. Dipole – same # π electrons (4), different # atoms (4 vs. 3)b. Examples – azides, diazocompounds, nitrile oxides5. Ozonolysis – Most important dipolar cycloadditiona. Mechanism – [4+2], retro-[4+2], [4+2]. (Then reduction or oxidation withadditional reagentb. Zn or (CH3)2S gives carbonyls in oxidation state as is (after hydrolysis)c. NaBH4reduces aldehydes, ketones to alcoholsd. H2CrO4(Jones) oxidizes aldehyde to acid (no effect on ketone)C. Electrocyclic Reactions1. Introductory Examples - (E,Z)-2,4-hexadiene and (E,E)-2,4-hexadiene2. Definitionsa. Concerted pericyclic processb. Cyclic transition statec. Intramolecular, i.e. 1 overlapping array of orbitalsd. Formation/Breaking of 1 sigma bond3. FMO Analysis of Stereochemical Results (see examples in A, above)a. (Thermal) (E,Z)-2,4-hexadiene –> cis–3,4-dimethylcyclobutene(conrotatory) and (E,E)-2,4-hexadiene, thermal –> trans–3,4-dimethylcyclobutene (conrotatory).b. (Photochemical) (E,Z)-2,4-hexadiene, –> trans–3,4-dimethylcyclobutene -electron promoted to higher energy orbital; thus HOMO is different than inthermal reactions. (disrotatory) and (E,E)-2,4-hexadiene –> cis–3,4-dimethylcyclobutene - electron promoted to higher energy orbital; thusHOMO is different than in thermal reactions. (disrotatory)4. Electrocyclic Ring Opening – W-H rules still applya. trans–3,4-dimethylcyclobutene, thermal -> (E,E) -2,4-hexadiene(conrotatory)b. cis–3,4-dimethylcyclobutene, thermal -> (E,Z) -2,4-hexadiene(conrotatory)5. Electrocyclic Reactions Involving 6π Electronsa. (E,Z,E)-2,4,6-octatriene, thermal -> cis–5,6-dimethyl-1,3-cyclohexadiene(disrotatory)b. (E,Z,E)-2,4,6-octatriene, photochemical -> trans–5,6-dimethyl-1,3-cyclohexadiene - electron promoted to higher energy orbital; thus HOMO isdifferent than in thermal reactions. (conrotatory)c. Found in Vitamin D synthesisD. Sigmatropic Rearrangements1. Definitionsa. Concerted pericyclic processb. Cyclic transition statec. Intramolecular, i.e. 1 overlapping orbital arrayd. One sigma bond formed, one brokene. [i,j] – i + j = number of atoms in orbital arrayi, j = number of atoms on either side of sigma bond broken (or formed)2. Cope Rearrangement, Thermal [3,3]a. Thermodynamically driveni. Alkene substitutionii. Ring strain3. Claisen Rearrangement, Thermal [3,3]4. Woodward-Hoffmann Rules5. Thermal [1,5] H-Shift6. Thermal [1,3] H-Shift7. Thermal [1,7] H-ShiftGood Luck on the Exam!– Tim Jamison –。

物理学专业英语

华中师范大学物理学院物理学专业英语仅供内部学习参考！2014一、课程的任务和教学目的通过学习《物理学专业英语》，学生将掌握物理学领域使用频率较高的专业词汇和表达方法，进而具备基本的阅读理解物理学专业文献的能力。

通过分析《物理学专业英语》课程教材中的范文，学生还将从英语角度理解物理学中个学科的研究内容和主要思想，提高学生的专业英语能力和了解物理学研究前沿的能力。

培养专业英语阅读能力，了解科技英语的特点，提高专业外语的阅读质量和阅读速度；掌握一定量的本专业英文词汇，基本达到能够独立完成一般性本专业外文资料的阅读；达到一定的笔译水平。

要求译文通顺、准确和专业化。

二、课程内容课程内容包括以下章节：物理学、经典力学、热力学、电磁学、光学、原子物理、统计力学、量子力学和狭义相对论三、基本要求1.充分利用课内时间保证充足的阅读量（约1200~1500词/学时），要求正确理解原文。

2.泛读适量课外相关英文读物，要求基本理解原文主要内容。

3.掌握基本专业词汇（不少于200词）。

4.应具有流利阅读、翻译及赏析专业英语文献，并能简单地进行写作的能力。

四、参考书目录1 Physics 物理学 (1)Introduction to physics (1)Classical and modern physics (2)Research fields (4)V ocabulary (7)2 Classical mechanics 经典力学 (10)Introduction (10)Description of classical mechanics (10)Momentum and collisions (14)Angular momentum (15)V ocabulary (16)3 Thermodynamics 热力学 (18)Introduction (18)Laws of thermodynamics (21)System models (22)Thermodynamic processes (27)Scope of thermodynamics (29)V ocabulary (30)4 Electromagnetism 电磁学 (33)Introduction (33)Electrostatics (33)Magnetostatics (35)Electromagnetic induction (40)V ocabulary (43)5 Optics 光学 (45)Introduction (45)Geometrical optics (45)Physical optics (47)Polarization (50)V ocabulary (51)6 Atomic physics 原子物理 (52)Introduction (52)Electronic configuration (52)Excitation and ionization (56)V ocabulary (59)7 Statistical mechanics 统计力学 (60)Overview (60)Fundamentals (60)Statistical ensembles (63)V ocabulary (65)8 Quantum mechanics 量子力学 (67)Introduction (67)Mathematical formulations (68)Quantization (71)Wave-particle duality (72)Quantum entanglement (75)V ocabulary (77)9 Special relativity 狭义相对论 (79)Introduction (79)Relativity of simultaneity (80)Lorentz transformations (80)Time dilation and length contraction (81)Mass-energy equivalence (82)Relativistic energy-momentum relation (86)V ocabulary (89)正文标记说明：蓝色Arial字体（例如energy）：已知的专业词汇蓝色Arial字体加下划线（例如electromagnetism）：新学的专业词汇黑色Times New Roman字体加下划线（例如postulate）：新学的普通词汇1 Physics 物理学1 Physics 物理学Introduction to physicsPhysics is a part of natural philosophy and a natural science that involves the study of matter and its motion through space and time, along with related concepts such as energy and force. More broadly, it is the general analysis of nature, conducted in order to understand how the universe behaves.Physics is one of the oldest academic disciplines, perhaps the oldest through its inclusion of astronomy. Over the last two millennia, physics was a part of natural philosophy along with chemistry, certain branches of mathematics, and biology, but during the Scientific Revolution in the 17th century, the natural sciences emerged as unique research programs in their own right. Physics intersects with many interdisciplinary areas of research, such as biophysics and quantum chemistry,and the boundaries of physics are not rigidly defined. New ideas in physics often explain the fundamental mechanisms of other sciences, while opening new avenues of research in areas such as mathematics and philosophy.Physics also makes significant contributions through advances in new technologies that arise from theoretical breakthroughs. For example, advances in the understanding of electromagnetism or nuclear physics led directly to the development of new products which have dramatically transformed modern-day society, such as television, computers, domestic appliances, and nuclear weapons; advances in thermodynamics led to the development of industrialization; and advances in mechanics inspired the development of calculus.Core theoriesThough physics deals with a wide variety of systems, certain theories are used by all physicists. Each of these theories were experimentally tested numerous times and found correct as an approximation of nature (within a certain domain of validity).For instance, the theory of classical mechanics accurately describes the motion of objects, provided they are much larger than atoms and moving at much less than the speed of light. These theories continue to be areas of active research, and a remarkable aspect of classical mechanics known as chaos was discovered in the 20th century, three centuries after the original formulation of classical mechanics by Isaac Newton (1642–1727) 【艾萨克·牛顿】.University PhysicsThese central theories are important tools for research into more specialized topics, and any physicist, regardless of his or her specialization, is expected to be literate in them. These include classical mechanics, quantum mechanics, thermodynamics and statistical mechanics, electromagnetism, and special relativity.Classical and modern physicsClassical mechanicsClassical physics includes the traditional branches and topics that were recognized and well-developed before the beginning of the 20th century—classical mechanics, acoustics, optics, thermodynamics, and electromagnetism.Classical mechanics is concerned with bodies acted on by forces and bodies in motion and may be divided into statics (study of the forces on a body or bodies at rest), kinematics (study of motion without regard to its causes), and dynamics (study of motion and the forces that affect it); mechanics may also be divided into solid mechanics and fluid mechanics (known together as continuum mechanics), the latter including such branches as hydrostatics, hydrodynamics, aerodynamics, and pneumatics.Acoustics is the study of how sound is produced, controlled, transmitted and received. Important modern branches of acoustics include ultrasonics, the study of sound waves of very high frequency beyond the range of human hearing; bioacoustics the physics of animal calls and hearing, and electroacoustics, the manipulation of audible sound waves using electronics.Optics, the study of light, is concerned not only with visible light but also with infrared and ultraviolet radiation, which exhibit all of the phenomena of visible light except visibility, e.g., reflection, refraction, interference, diffraction, dispersion, and polarization of light.Heat is a form of energy, the internal energy possessed by the particles of which a substance is composed; thermodynamics deals with the relationships between heat and other forms of energy.Electricity and magnetism have been studied as a single branch of physics since the intimate connection between them was discovered in the early 19th century; an electric current gives rise to a magnetic field and a changing magnetic field induces an electric current. Electrostatics deals with electric charges at rest, electrodynamics with moving charges, and magnetostatics with magnetic poles at rest.Modern PhysicsClassical physics is generally concerned with matter and energy on the normal scale of1 Physics 物理学observation, while much of modern physics is concerned with the behavior of matter and energy under extreme conditions or on the very large or very small scale.For example, atomic and nuclear physics studies matter on the smallest scale at which chemical elements can be identified.The physics of elementary particles is on an even smaller scale, as it is concerned with the most basic units of matter; this branch of physics is also known as high-energy physics because of the extremely high energies necessary to produce many types of particles in large particle accelerators. On this scale, ordinary, commonsense notions of space, time, matter, and energy are no longer valid.The two chief theories of modern physics present a different picture of the concepts of space, time, and matter from that presented by classical physics.Quantum theory is concerned with the discrete, rather than continuous, nature of many phenomena at the atomic and subatomic level, and with the complementary aspects of particles and waves in the description of such phenomena.The theory of relativity is concerned with the description of phenomena that take place in a frame of reference that is in motion with respect to an observer; the special theory of relativity is concerned with relative uniform motion in a straight line and the general theory of relativity with accelerated motion and its connection with gravitation.Both quantum theory and the theory of relativity find applications in all areas of modern physics.Difference between classical and modern physicsWhile physics aims to discover universal laws, its theories lie in explicit domains of applicability. Loosely speaking, the laws of classical physics accurately describe systems whose important length scales are greater than the atomic scale and whose motions are much slower than the speed of light. Outside of this domain, observations do not match their predictions.Albert Einstein【阿尔伯特·爱因斯坦】contributed the framework of special relativity, which replaced notions of absolute time and space with space-time and allowed an accurate description of systems whose components have speeds approaching the speed of light.Max Planck【普朗克】, Erwin Schrödinger【薛定谔】, and others introduced quantum mechanics, a probabilistic notion of particles and interactions that allowed an accurate description of atomic and subatomic scales.Later, quantum field theory unified quantum mechanics and special relativity.General relativity allowed for a dynamical, curved space-time, with which highly massiveUniversity Physicssystems and the large-scale structure of the universe can be well-described. General relativity has not yet been unified with the other fundamental descriptions; several candidate theories of quantum gravity are being developed.Research fieldsContemporary research in physics can be broadly divided into condensed matter physics; atomic, molecular, and optical physics; particle physics; astrophysics; geophysics and biophysics. Some physics departments also support research in Physics education.Since the 20th century, the individual fields of physics have become increasingly specialized, and today most physicists work in a single field for their entire careers. "Universalists" such as Albert Einstein (1879–1955) and Lev Landau (1908–1968)【列夫·朗道】, who worked in multiple fields of physics, are now very rare.Condensed matter physicsCondensed matter physics is the field of physics that deals with the macroscopic physical properties of matter. In particular, it is concerned with the "condensed" phases that appear whenever the number of particles in a system is extremely large and the interactions between them are strong.The most familiar examples of condensed phases are solids and liquids, which arise from the bonding by way of the electromagnetic force between atoms. More exotic condensed phases include the super-fluid and the Bose–Einstein condensate found in certain atomic systems at very low temperature, the superconducting phase exhibited by conduction electrons in certain materials,and the ferromagnetic and antiferromagnetic phases of spins on atomic lattices.Condensed matter physics is by far the largest field of contemporary physics.Historically, condensed matter physics grew out of solid-state physics, which is now considered one of its main subfields. The term condensed matter physics was apparently coined by Philip Anderson when he renamed his research group—previously solid-state theory—in 1967. In 1978, the Division of Solid State Physics of the American Physical Society was renamed as the Division of Condensed Matter Physics.Condensed matter physics has a large overlap with chemistry, materials science, nanotechnology and engineering.Atomic, molecular and optical physicsAtomic, molecular, and optical physics (AMO) is the study of matter–matter and light–matter interactions on the scale of single atoms and molecules.1 Physics 物理学The three areas are grouped together because of their interrelationships, the similarity of methods used, and the commonality of the energy scales that are relevant. All three areas include both classical, semi-classical and quantum treatments; they can treat their subject from a microscopic view (in contrast to a macroscopic view).Atomic physics studies the electron shells of atoms. Current research focuses on activities in quantum control, cooling and trapping of atoms and ions, low-temperature collision dynamics and the effects of electron correlation on structure and dynamics. Atomic physics is influenced by the nucleus (see, e.g., hyperfine splitting), but intra-nuclear phenomena such as fission and fusion are considered part of high-energy physics.Molecular physics focuses on multi-atomic structures and their internal and external interactions with matter and light.Optical physics is distinct from optics in that it tends to focus not on the control of classical light fields by macroscopic objects, but on the fundamental properties of optical fields and their interactions with matter in the microscopic realm.High-energy physics (particle physics) and nuclear physicsParticle physics is the study of the elementary constituents of matter and energy, and the interactions between them.In addition, particle physicists design and develop the high energy accelerators,detectors, and computer programs necessary for this research. The field is also called "high-energy physics" because many elementary particles do not occur naturally, but are created only during high-energy collisions of other particles.Currently, the interactions of elementary particles and fields are described by the Standard Model.●The model accounts for the 12 known particles of matter (quarks and leptons) thatinteract via the strong, weak, and electromagnetic fundamental forces.●Dynamics are described in terms of matter particles exchanging gauge bosons (gluons,W and Z bosons, and photons, respectively).●The Standard Model also predicts a particle known as the Higgs boson. In July 2012CERN, the European laboratory for particle physics, announced the detection of a particle consistent with the Higgs boson.Nuclear Physics is the field of physics that studies the constituents and interactions of atomic nuclei. The most commonly known applications of nuclear physics are nuclear power generation and nuclear weapons technology, but the research has provided application in many fields, including those in nuclear medicine and magnetic resonance imaging, ion implantation in materials engineering, and radiocarbon dating in geology and archaeology.University PhysicsAstrophysics and Physical CosmologyAstrophysics and astronomy are the application of the theories and methods of physics to the study of stellar structure, stellar evolution, the origin of the solar system, and related problems of cosmology. Because astrophysics is a broad subject, astrophysicists typically apply many disciplines of physics, including mechanics, electromagnetism, statistical mechanics, thermodynamics, quantum mechanics, relativity, nuclear and particle physics, and atomic and molecular physics.The discovery by Karl Jansky in 1931 that radio signals were emitted by celestial bodies initiated the science of radio astronomy. Most recently, the frontiers of astronomy have been expanded by space exploration. Perturbations and interference from the earth's atmosphere make space-based observations necessary for infrared, ultraviolet, gamma-ray, and X-ray astronomy.Physical cosmology is the study of the formation and evolution of the universe on its largest scales. Albert Einstein's theory of relativity plays a central role in all modern cosmological theories. In the early 20th century, Hubble's discovery that the universe was expanding, as shown by the Hubble diagram, prompted rival explanations known as the steady state universe and the Big Bang.The Big Bang was confirmed by the success of Big Bang nucleo-synthesis and the discovery of the cosmic microwave background in 1964. The Big Bang model rests on two theoretical pillars: Albert Einstein's general relativity and the cosmological principle (On a sufficiently large scale, the properties of the Universe are the same for all observers). Cosmologists have recently established the ΛCDM model (the standard model of Big Bang cosmology) of the evolution of the universe, which includes cosmic inflation, dark energy and dark matter.Current research frontiersIn condensed matter physics, an important unsolved theoretical problem is that of high-temperature superconductivity. Many condensed matter experiments are aiming to fabricate workable spintronics and quantum computers.In particle physics, the first pieces of experimental evidence for physics beyond the Standard Model have begun to appear. Foremost among these are indications that neutrinos have non-zero mass. These experimental results appear to have solved the long-standing solar neutrino problem, and the physics of massive neutrinos remains an area of active theoretical and experimental research. Particle accelerators have begun probing energy scales in the TeV range, in which experimentalists are hoping to find evidence for the super-symmetric particles, after discovery of the Higgs boson.Theoretical attempts to unify quantum mechanics and general relativity into a single theory1 Physics 物理学of quantum gravity, a program ongoing for over half a century, have not yet been decisively resolved. The current leading candidates are M-theory, superstring theory and loop quantum gravity.Many astronomical and cosmological phenomena have yet to be satisfactorily explained, including the existence of ultra-high energy cosmic rays, the baryon asymmetry, the acceleration of the universe and the anomalous rotation rates of galaxies.Although much progress has been made in high-energy, quantum, and astronomical physics, many everyday phenomena involving complexity, chaos, or turbulence are still poorly understood. Complex problems that seem like they could be solved by a clever application of dynamics and mechanics remain unsolved; examples include the formation of sand-piles, nodes in trickling water, the shape of water droplets, mechanisms of surface tension catastrophes, and self-sorting in shaken heterogeneous collections.These complex phenomena have received growing attention since the 1970s for several reasons, including the availability of modern mathematical methods and computers, which enabled complex systems to be modeled in new ways. Complex physics has become part of increasingly interdisciplinary research, as exemplified by the study of turbulence in aerodynamics and the observation of pattern formation in biological systems.Vocabulary★natural science 自然科学academic disciplines 学科astronomy 天文学in their own right 凭他们本身的实力intersects相交，交叉interdisciplinary交叉学科的，跨学科的★quantum 量子的theoretical breakthroughs 理论突破★electromagnetism 电磁学dramatically显著地★thermodynamics热力学★calculus微积分validity★classical mechanics 经典力学chaos 混沌literate 学者★quantum mechanics量子力学★thermodynamics and statistical mechanics热力学与统计物理★special relativity狭义相对论is concerned with 关注，讨论，考虑acoustics 声学★optics 光学statics静力学at rest 静息kinematics运动学★dynamics动力学ultrasonics超声学manipulation 操作，处理，使用University Physicsinfrared红外ultraviolet紫外radiation辐射reflection 反射refraction 折射★interference 干涉★diffraction 衍射dispersion散射★polarization 极化，偏振internal energy 内能Electricity电性Magnetism 磁性intimate 亲密的induces 诱导，感应scale尺度★elementary particles基本粒子★high-energy physics 高能物理particle accelerators 粒子加速器valid 有效的，正当的★discrete离散的continuous 连续的complementary 互补的★frame of reference 参照系★the special theory of relativity 狭义相对论★general theory of relativity 广义相对论gravitation 重力，万有引力explicit 详细的，清楚的★quantum field theory 量子场论★condensed matter physics凝聚态物理astrophysics天体物理geophysics地球物理Universalist博学多才者★Macroscopic宏观Exotic奇异的★Superconducting 超导Ferromagnetic铁磁质Antiferromagnetic 反铁磁质★Spin自旋Lattice 晶格，点阵，网格★Society社会，学会★microscopic微观的hyperfine splitting超精细分裂fission分裂，裂变fusion熔合，聚变constituents成分，组分accelerators加速器detectors 检测器★quarks夸克lepton 轻子gauge bosons规范玻色子gluons胶子★Higgs boson希格斯玻色子CERN欧洲核子研究中心★Magnetic Resonance Imaging磁共振成像，核磁共振ion implantation 离子注入radiocarbon dating放射性碳年代测定法geology地质学archaeology考古学stellar 恒星cosmology宇宙论celestial bodies 天体Hubble diagram 哈勃图Rival竞争的★Big Bang大爆炸nucleo-synthesis核聚合，核合成pillar支柱cosmological principle宇宙学原理ΛCDM modelΛ-冷暗物质模型cosmic inflation宇宙膨胀1 Physics 物理学fabricate制造，建造spintronics自旋电子元件，自旋电子学★neutrinos 中微子superstring 超弦baryon重子turbulence湍流，扰动，骚动catastrophes突变，灾变，灾难heterogeneous collections异质性集合pattern formation模式形成University Physics2 Classical mechanics 经典力学IntroductionIn physics, classical mechanics is one of the two major sub-fields of mechanics, which is concerned with the set of physical laws describing the motion of bodies under the action of a system of forces. The study of the motion of bodies is an ancient one, making classical mechanics one of the oldest and largest subjects in science, engineering and technology.Classical mechanics describes the motion of macroscopic objects, from projectiles to parts of machinery, as well as astronomical objects, such as spacecraft, planets, stars, and galaxies. Besides this, many specializations within the subject deal with gases, liquids, solids, and other specific sub-topics.Classical mechanics provides extremely accurate results as long as the domain of study is restricted to large objects and the speeds involved do not approach the speed of light. When the objects being dealt with become sufficiently small, it becomes necessary to introduce the other major sub-field of mechanics, quantum mechanics, which reconciles the macroscopic laws of physics with the atomic nature of matter and handles the wave–particle duality of atoms and molecules. In the case of high velocity objects approaching the speed of light, classical mechanics is enhanced by special relativity. General relativity unifies special relativity with Newton's law of universal gravitation, allowing physicists to handle gravitation at a deeper level.The initial stage in the development of classical mechanics is often referred to as Newtonian mechanics, and is associated with the physical concepts employed by and the mathematical methods invented by Newton himself, in parallel with Leibniz【莱布尼兹】, and others.Later, more abstract and general methods were developed, leading to reformulations of classical mechanics known as Lagrangian mechanics and Hamiltonian mechanics. These advances were largely made in the 18th and 19th centuries, and they extend substantially beyond Newton's work, particularly through their use of analytical mechanics. Ultimately, the mathematics developed for these were central to the creation of quantum mechanics.Description of classical mechanicsThe following introduces the basic concepts of classical mechanics. For simplicity, it often2 Classical mechanics 经典力学models real-world objects as point particles, objects with negligible size. The motion of a point particle is characterized by a small number of parameters: its position, mass, and the forces applied to it.In reality, the kind of objects that classical mechanics can describe always have a non-zero size. (The physics of very small particles, such as the electron, is more accurately described by quantum mechanics). Objects with non-zero size have more complicated behavior than hypothetical point particles, because of the additional degrees of freedom—for example, a baseball can spin while it is moving. However, the results for point particles can be used to study such objects by treating them as composite objects, made up of a large number of interacting point particles. The center of mass of a composite object behaves like a point particle.Classical mechanics uses common-sense notions of how matter and forces exist and interact. It assumes that matter and energy have definite, knowable attributes such as where an object is in space and its speed. It also assumes that objects may be directly influenced only by their immediate surroundings, known as the principle of locality.In quantum mechanics objects may have unknowable position or velocity, or instantaneously interact with other objects at a distance.Position and its derivativesThe position of a point particle is defined with respect to an arbitrary fixed reference point, O, in space, usually accompanied by a coordinate system, with the reference point located at the origin of the coordinate system. It is defined as the vector r from O to the particle.In general, the point particle need not be stationary relative to O, so r is a function of t, the time elapsed since an arbitrary initial time.In pre-Einstein relativity (known as Galilean relativity), time is considered an absolute, i.e., the time interval between any given pair of events is the same for all observers. In addition to relying on absolute time, classical mechanics assumes Euclidean geometry for the structure of space.Velocity and speedThe velocity, or the rate of change of position with time, is defined as the derivative of the position with respect to time. In classical mechanics, velocities are directly additive and subtractive as vector quantities; they must be dealt with using vector analysis.When both objects are moving in the same direction, the difference can be given in terms of speed only by ignoring direction.University PhysicsAccelerationThe acceleration , or rate of change of velocity, is the derivative of the velocity with respect to time (the second derivative of the position with respect to time).Acceleration can arise from a change with time of the magnitude of the velocity or of the direction of the velocity or both . If only the magnitude v of the velocity decreases, this is sometimes referred to as deceleration , but generally any change in the velocity with time, including deceleration, is simply referred to as acceleration.Inertial frames of referenceWhile the position and velocity and acceleration of a particle can be referred to any observer in any state of motion, classical mechanics assumes the existence of a special family of reference frames in terms of which the mechanical laws of nature take a comparatively simple form. These special reference frames are called inertial frames .An inertial frame is such that when an object without any force interactions (an idealized situation) is viewed from it, it appears either to be at rest or in a state of uniform motion in a straight line. This is the fundamental definition of an inertial frame. They are characterized by the requirement that all forces entering the observer's physical laws originate in identifiable sources (charges, gravitational bodies, and so forth).A non-inertial reference frame is one accelerating with respect to an inertial one, and in such a non-inertial frame a particle is subject to acceleration by fictitious forces that enter the equations of motion solely as a result of its accelerated motion, and do not originate in identifiable sources. These fictitious forces are in addition to the real forces recognized in an inertial frame.A key concept of inertial frames is the method for identifying them. For practical purposes, reference frames that are un-accelerated with respect to the distant stars are regarded as good approximations to inertial frames.Forces; Newton's second lawNewton was the first to mathematically express the relationship between force and momentum . Some physicists interpret Newton's second law of motion as a definition of force and mass, while others consider it a fundamental postulate, a law of nature. Either interpretation has the same mathematical consequences, historically known as "Newton's Second Law":a m t v m t p F ===d )(d d dThe quantity m v is called the (canonical ) momentum . The net force on a particle is thus equal to rate of change of momentum of the particle with time.So long as the force acting on a particle is known, Newton's second law is sufficient to。

MIT-SCIENCE-Lectures-lec13a

where �b is the buoyancy diﬀerence across the base of the mixed layer. Then the rate of increasing PE is P Efe = �bhwe /2 (12.7) where we = dh/dt, the entrainment velocity. Energy balance If the rate of increase of PE due to entrainment is equal to the TKE ﬂuxes due to buoyancy forcing and wind stress (minus that component lost to dissipation) then P Efe = T KEfw + T KEfb± B 0 + |B 0 | B0 − |B0 | +n �bwe h/2 = mu + 2 2
Course requirements Class attendance and discussion, bi-weekly homework assignments, ﬁnal exam.
Reference texts Andrews, Holton, and Leovy, “Middle atmosphere dynamics”
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If the buoyancy ﬂux is stabilizing and suﬃciently strong to counteract the eﬀect of the wind, then this will give we < 0. In this case, h is reduced so that we = 0. This gives 2mu�3 h= (12.10) −B0 This agrees with the Monin-Obukhov length scale if m = 1/(2�) = 1.25. The tracers in the m.l. are then modiﬁed by entrainment:

MIT-SCIENCE-Lectures-lec1present

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哈佛大学高等有机化学讲义Lecture15

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7.88 Lecture Notes - 157.24/7.88J/5.48JThe Protein Folding ProblemRibosomes and In Vivo FoldingA. RibosomesRibosomes: Source of all Proteins!In prokaryotes, all ribosomes within cytoplasm;However, multiple delivery compartments:• PP chains >> cytoplasm• PP Chains >> inner membrane• PP chains >> organelles e.g. flagellum• PP chains >> through membrane to periplasm• PP chains >> through membrane and periplasm to outer membrane• PP chains >> secreted outside cell.Export pathways use protein channels - poorly defined, very active area of research;Polypeptide chains have a leader sequence whose recognition brings them to channel; this is recognized by a leader peptidase, which cleaves off leader sequence, coupled to transit.In Eukaryotes:• Cytoplasm• Exported through Endoplasmic reticuluum (Signal Recognition Particle) > Golgi> export• Imported into Mitochondria or chloroplasts• Translocated to Nucleus• Inserted into Membranes:• Many others, e.g. lysosomesRate of Prokaryotic Cytoplasmic Protein Synthesis:Forschammer and Lindahl (1971) J. Mol. Biol. 55, 563-568.• About 20,000 ribosomes/cell in rapidly growing E. coli• Rate of synthesis = 21aa/second/ribosome in coli growing in broth at 37o C.Slower growth rates:Carbon Source RateSuccinate 16/sec Glucose 21/sec Acetate 12/sec Casamino acids 20/secRibosomes proceed 5’ to 3’ down mRNA.In eukaryotes, generally 3-5 fold slower – {3-6 amino acids/second (soft number}: Morphology and Composition of 70s Prokaryotic Ribosomes:E. coli bacteria:• Small 30s and large 50s subunits;• 2.6 x 106 Daltons total;• RNA: Protein 2:1 by weight;• RNA as Mg++ salt;• Only 1gmH20/gm ribosomes - compact, dense;• 1 each of 53 protein chains30S subunit:wt.Protein Mol.RNA16s RNA - 1542 bases: 21 diff. Chains 1.0 x106 120A x 230 A50S subunit:23s RNA - 2904 bases 34 diff. Chains 1. 7 x 106 60A x 220 x 220A 5s RNA -120 bases.Largest protein: S1, 557aaSmallest: L34, 46 aaOnly one protein in common to both subunits (S20 = L26).Little sequence similarity.Composition Eukaryotic 80S Ribsome:Two subunits small 40s and large 60s;More protein than prokaryotes:RNA: Protein ratio, closer to 1:1;Eighty + species of protein chains!Subunits:40S:18s RNA -1874 bases; 33 proteins60S:28s – 4718 bases; 49 proteins5.8Ss - 160; and 5S (*120) RNAsChloroplast and Mitochondrial ribosomes closer to prokaryotic.A note on ribosomal proteins:• Not globular soluble; not fibrous:• Fold together with RNA! True two component system, one is not chaperone of the other• Masayasu Nomura in 1970s.Anatomy of 50S:Central protuberance or head: (location of 5SRNA)L7/L12 stalkL1 RidgePeptidyl transferase site; central protuberance of large subunitFunctional Anatomy of 30S:Base or body; Distinctive head: lateral platform, defined by groove.30S Platform opposes L1 ridge in 70S; head to head.Head and stalk of 70S not covered by 50SInitiation factor binding + Cleft of small subunitMessenger binding site = platform of small subunitTranslocation Factors, Peptidyltransferase, 5S sites = inside face of head of 50S, base of L7/L12 stalkGTP dependent translocation steps = L7/L12 stalk:Where does Peptide Bond Formation Occur?tRNA; anticodon loop on 30S subunit encountering mRNA; but amino acyl site down in L7/L12 stalkWhat is environment of newly synthesized chain?Aqueous or protected from solvent?B. Stereochemistry of synthesisV. I. Lim and A. S. Spirin (1986) J. MB 188, 565-577:Assume Sn2 nucleophilic substitution reaction;• Peptidyl tRNA is in donor site;• amino acyl tRNA is in acceptor site.• After covalent bond formed nascent chain is passed to amino acyl tRNA;• Amino group of amino acyl tRNA is active nucleophile which attacks carbonyl of ester of donor tRNA;• generates acyl of generating tetrahedral intermediate;• Has to be sterically acceptible for all 400 pairwise reactions for 20 amino acids.Explore all angles; conclude only one conformation of newly synthesized peptide doesn’t violate: alpha helix!• Newly synthesized sequence is alpha helical independently of sequence.• Ribosome channel is designed to transmit alpha-helical conformation. Where does newly synthesized polypeptide chain emerge from ribosome? Location of exit site:• 30-40 amino acids protected from protease degradation by ribosome itself (Smith, Tai, and Davis, 1978, PNAS, 75, 5922-5925.)>>Channel?• If there is a channel, where does nascent chain exit?Answered with recent solution of ribosome structure by EM and X-ray diffraction: Prepare antibody to beta-galactosidase;>>Isolate ribosomes synthesizing beta gal; >>treat fractions with antibody;>>centrifuge and examine dimers in EMUse E. coli synthesizing high level of beta galactosidase: Tetramer of 465,000 total.Lyse cells, fractionate ribosomes and polysomes by sucrose gradient centrifugation:Absorption at 260 on left axisFraction number on X axis, 1-15.Monosome peak followed by polysome peak peaking at about 10 ribosomes. Activity assay peaks at fraction 7-8Now incubate with RNase to break down messenger, generate all monosomes: Incubate with anti-beta gal, recentrifuge:Most ribosomes not shifted, but beta galactosidase activity now shifts to disome sedimentation.This activity is released by treatment of puromycin which releases nascent chains:LNow for morphological experiment:Incubate polysomes with antibody; Resediment and look for disome peak: Prepare for electron microscopy:Find lots of pairs; butts facing each other. So back site is exist:They estimate 150 A from transpeptidation site. If 30-40 protected, can't be alpha helical, 40 x 1.5 = 60A°.What about epitope and antibody??Exit site= membrane binding site.Technical problem; require epitope; perhaps epitope does not correspond to exit sites.Most recent work:A.S. Spirin Ryabova et al, FEBS Letters (1988) 226, 255-260.They conclude exit site is close to peptidyl transferase site, may wind on ribosome surface.Perhaps exit site is protein folding site.!!??Nenad Ban, Poul Nissen, Jeffrey Hansen,m Malcolm Capel, Peter B. Moore and Thomas A. Steitz (1999) “Placement of protein and RNA structures into a 5A resolution map of the 50S ribosomal subunit” Nature 400, 841-847.“At the bottom of the active-site cleft is a tunnel that runs straight through the subunit. In one of our heavy-atom derivatized crystals, the path of this tunnel ismarked by the positions of four bond eleven-tungsten (W11)-cluster molecules, which have a van der Waals diameter of nearly 20A and lie on an almost straight line (Fig.2). This tunnel is thought to be the path used by the nascent chain polypeptide chain to traverse from the peptidyltransferase centre to the point where it leaves the ribosome, an idea supported by the location at the tunnel entrance of the amino acyl end of formyl-methionine f(Met)-tRNA bound at the P site and the alignment of the tunnel exit on the back of the large subunit with the central pore of the Sec61 channel in yeast.”Conformation of nascent chain:Not enough known to be worth reporting;• Epitopes can fold in nascent chain• Many proteins, N-terminus is dispensable, so not playing key nucleating role.To what compartment is protein targeted?• Cytoplasm• Periplasm• ExportSo successful transit requires the chain not reach native conformation:SecB >>tetramer; binds newly synthesized chain for many proteins; Does not bind correctly folded native state.Chaperonin>>retard folding (Linda Randall)SecB protein recC. Folding Pathways evolved through biological evolutionBiologically evolved process: No reason to expect or believe that there is a unitary mechanism! Reptiles evolved in hot climates; but living North American reptiles and amphibians – frogs, salamanders, turtles - adapted to ice ages; may well retain features of folding intermediates only needed at higher temperatures, but still retained in current physiology: “relic features”NS >> [I ]1 >>[I]2 >> N = f(salts, concentration, temperature, pH, cofactors) May have one mechanism, pathway dominant at one temperature, second under other conditions;Example: Collagen;In mammals, clearly folding and chain association f (extent of hydroxylation).But! Collagens from cold-blooded creatures have very low levels of hydroxyproline; yet still form collagen, still Tm f {proline rings}Triple helix driven at low temp by glycines and prolinesDriven at high temperature by extent of hydroxylation of prolines!One pathway in bacterial cells, another in red blood cells!Very general result that folding dependent on environmental context:When faced with problems in recovering folded protein, understanding process is critical:• In what cells are proteins synthesized?• What cell compartments does the chain pass through?• In which compartment does it achieve its native state?• What is form of chain that is released from ribosomes:• cf collagen/cytochrome c/insulin。