Baker Paper List and Comments Principles for designing ideal protein structures Create a set of rules for

2-structure folding (BB,aB,Ba) based from PDB structures Recreate them from hard-sphere modeling Computational Design of Self-Assembling Protein Nanomaterials with Atomic Level Accuracy Most rotamers in O3-33 are way off "interactions between the subunits are required to drive assembly... coiled-coil and helical bundle interactions (7 11)" 07. B. Lovejoy et al., Science 259, 1288 (1993). 08. P. B. Harbury, J. J. Plecs, B. Tidor, T. Alber, P. S. Kim, S cience 282, 1462 (1998). 09. C. Gribbon et al., Biochemistry 47, 10365 (2008). 10. N. R. Zaccai et al., Nat. Chem. Biol. 7, 935 (2011). 11. R. L. Koder et al., Nature 458, 305 (2009) "genetic fusion of multiple protein domains or fragments that naturally. .. self-associate (18, 19)" 18. J. E. Padilla, C. Colovos, T. O. Yeates, Proc. Natl. Acad. S ci. U.S.A. 98, 2217 (2001). 19. J. C. Sinclair, K. M. Davies, C. Vnien-Bryan, M. E. Noble, Na t. Nanotechnol. 6, 558 (2011). "In contrast, natural protein assemblies are most often held together by many weak, noncovalent interactions which together form large, highly comple mentary, low-energy protein-protein interfaces (20)." 20. J. Janin, R. P. Bahadur, P. Chakrabarti, Q. Rev. Biophys. 41 , 133 (2008). "However, recent advances (22 26), including the de novo design of a heterodimeric protein interface with atomic level accuracy (27, 28), su ggest that our ability to computationally model and design protein-protein interactions is rapidly maturing." 22. T. Kortemme et al., Nat. Struct. Mol. Biol. 11, 371 (2004). 23. P. S. Huang, J. J. Love, S. L. Mayo, Protein Sci. 16, 2770 ( 2007). 24. R. K. Jha et al., J. Mol. Biol. 400, 257 (2010). 25. J. Karanicolas et al., Mol. Cell 42, 250 (2011). 26. P. B. Stranges, M. Machius, M. J. Miley, A. Tripathy, B. Kuh lman, Proc. Natl. Acad. Sci. U.S.A. 108, 20562 (2011). 27. S. J. Fleishman et al., Science 332, 816 (2011). 28. S. J. Fleishman et al., J. Mol. Biol. 413, 1047 (2011). (Hemaglutinnin and self-Assembly, read) Entropic costs

21. D. Grueninger et al., Science 319, 206 (2008). WEIGH THE SIDE CHAINS BY MSA!!!!! 21. C. Cole, J. Warwicker, Protein Sci. 11, 2860 (2002). It may be expected that more favorable binding surfaces correlate with a smaller loss of side-chain conformational entropy and a larger burial of (nonpolar) surface area. The side chains of 21 out of the 25 homodimers were less flexible (up to 34.9%) at the interface than elsewhere. To test whether differential flexibility between interfa cial and noninterfacial residues for the homodimers was encoded s imply in residue types (in particular small, less flexible residues) the frequency of residue occurrence was plotted (Fig. 2). It is apparent that nonpolar residues (e.g., Leu, Met, Phe, Val) are generally more p revalent at the interface and that polar residues (i.e., Asp, Glu, Lys) are more common at the noninterfacial surface, INTERFACE AREAS HAVE A SMALL CHANGE IN CONFORMATIONAL EN TROPY (dS)!!!!! MIGHT BE ABLE TO PREDICT BINDING!!!!! 22. K. K. Frederick, M. S. Marlow, K. G. Valentine, A. J. Wand, Nature 448, 325 (2007). What is less understood is the potential entropic contri butions from a structured protein (dS^protein), which includes changes in its conformational entropy (dS^protein_conf) as well as chan ges in rotational and translational entropy (dS^protein_rot/trans) 5 7. The conformational entropy of proteins is manifested as motion between different structural states7. 5. Steinberg, I. Z. & Scheraga, H. A. Entropy changes ac companying association reactions of proteins.J. Biol. Chem. 238,172 181 (1963). 6. Cooper, A. & Dryden, D. T. F. Allostery without confo rmational change a plausible model. Eur. Biophys. J. Biophys. Lett.11,103 109 (198 4). 7. Karplus, M., Ichiye, T. & Pettitt, B. M. Configuratio nal entropy of native proteins. Biophys. J. 52, 1083 1085 (1987). 9. Igumenova, T. I., Frederick, K. K. & Wand, A. J. Char acterization of the fast dynamics of protein amino acid side chains using NMR re laxation in solution. Chem. Rev. 106,1672 1699 (2006).

24. Akke, M., Bruschweiler, R. & Palmer, A. G. NMR order parameters and free-energy an analytical approach and its application to cooper ative Ca21 binding by calbindin-D(9k). J. Am. Chem. Soc.115, 9832 9833 (1993). 25. Li, Z., Raychaudhuri, S. & Wand, A. J. Insights into the local residual entropy of proteins provided by NMR relaxation. Prot. Sci. 5 , 2647 2650 (1996). 26. Lee, A. L. et al.Temperature dependence of the inter nal dynamics of a calmodulinpeptide complex. Biochemistry 41,13814 13825 (2002). ##. Best, R. B., Clarke, J., & Karplus, M., What contrib utions to protein side-chain dynamics are probed by NMR experiments? A molecula r dynamics simulation analysis. J. Mol. Biol. 349, 185-203 (2005). ##. The role of conformational entropy in molecular recognition by calmodulin CaMtarget complexes have anchor residues that localize to hydrophobic pockets form ed by the amino and carboxy-terminal domains of CaM. Typically, one anchor residue is arom atic (Trp or Phe) and the other aliphatic. Anchor residues are believed to be essenti al for complex formation Clearly, binding does not induce a uniform reduction in side-chain motion within the hydrophobic pockets. More nuanced responses are also seen. This may be a feature of proteins that have evo lved to bind numerous targets. Such responses motivates extending the view of hot spot intera ctions 22 to include resolution of dynamical (entropic) from specific enthalpic contributions . 7,21,22,39-43,44!!! 7. Steinberg IZ, Scheraga HA. Entropy changes accompanyi ng association reactions of proteins. J. Biol. Chem. 1963; 238:172 81. [PubMed: 13 983721] 21. Crivici A, Ikura M. Molecular and structural basis o f target recognition by calmodulin. Annu. Rev. Biophys. Biomol. Struct. 1995; 24 :85 116. [PubMed: 7663132] 22. Clackson T, Wells JA. A hot spot of binding energy i n a hormone-receptor interface. Science. 1995; 267:383 6. [PubMed: 7529940] 39. Chatfield DC, Szabo A, Brooks BR. Molecular dynamics of staphylococcal nuclease: Comparison of simulation with N-15 and C-13 NMR rel axation data. J. Am. Chem. Soc. 1998; 120:5301 5311. 40. Prabhu NV, Lee AL, Wand AJ, Sharp KA. Dynamics and e ntropy of a calmodulin-peptide complex studied by NMR and molecular dynamics. Bi ochemistry. 2003; 42:562 570. [PubMed: 12525185] 41. Showalter SA, Bruschweiler R. Validation of molecula r dynamics simulations of biomolecules using NMR spin relaxation as benchmarks: Application to the AMBER99SB force field. J. Chem. Theory Comput. 2007; 3:961 975. 42. Li DW, Bruschweiler R. A dictionary for protein side -chain entropies from NMR order parameters. J. Am. Chem. Soc. 131:7226 7227. [PubM ed: 19422234] 43. Zhang F, Bruschweiler R. Contact model for the predi ction of NMR N-H order parameters in globular proteins. J. Am. Chem. Soc. 2008; 130:9178 9178.

44. Li DW, Bruschweiler R. In silico relationship betwee n configurational entropy and soft degrees of freedom in proteins and peptides. Phys. Rev. Lett. 2009; 102 Article Number: 118108. ##. The dark energy of proteins comes to light: conformational e ntropy and its role in protein function revealed by NMR relaxation NMR RELAXATION: FAST MOTIONS (SUB-NANOSEC) => LOTS OF ENTROPY NMR DISPERSION-RELAXATION: SLOW MOTIONS => NOT A LOT OF CONF ENTROPY Thesetypes or classes ofmotion often(butnot always)segregate into three distinct distributions of order parameters describing motion of the methyl symmetry axis (O 2 axis). The so-called J-class corresponds to side chain having signi?cant sub-nanosecond rotameric interconversion that leads to averaging of the J-coupling constant across the associated torsion angle. The w-class corresponds to side chain methyl groups showing highly restricted motion reminiscent of the backbone. The a-class arises from large amplitude motion within a single rotameric well and does not involve signi?cant (i.e. experimentally detectable) rotameric interconversion. 16. G. Lipari, A. Szabo. Model-free approach to the interpretation of nuclear ma gnetic-resonance relaxation in macromolecules. 1. Theory and range of validity. J Am Chem Soc, 104 (1982), pp. 4546 4559 17. M. Akke, R. Bruschweiler, A.G. Palmer. NMR order parameters and free-energy an analytical approach and its application to cooperative Ca2+ binding by calbin din-d(9k). J Am Chem Soc, 115 (1993), pp. 9832 9833 18. Z. Li, S. Raychaudhuri, A.J. Wand. Insights into the local residual entropy of proteins provided by NMR relaxation. Protein Sci, 5 (1996), pp. 2647 2650 19. D. Yang, L.E. Kay. Contributions to conformational entropy arising from bond vector fluctuations measured from NMR-derived order parameters: application to protein folding. J Mol Biol, 263 (1996), pp. 369 382

Protein activity regulation by conformational entropy Shiou-Ru Tzeng & Charalampos G. Kalodimos "S2 values are indicative of the amplitude of spatial fluctuations experienced by a bond vector and thus can be related to conformational entropy 21 23, as has previously been shown 3,4,24 27." 8. Hilser, V., Garcia-Moreno, E., Oas, T., Kapp, G. & Whitten, S. A Statistical Thermodynamic Model of the Protein Ensemble. Chem Rev 106, 1545 1558 (2006). 9. Marlow, M. S., Dogan, J., Frederick, K. K., Valentine, K. G. & Wand, A. J. Th e role of conformational entropy in molecular recognition by calmodulin. Nat Chem Biol 6, 352 358 (2010). 3. Sapienza, P. J. & Lee, A. L. Using NMR to study fast dynamics in proteins: me thods and applications. Curr. Opin. Pharmacol. 10, 723 730 (2010) 4. Tzeng, S.-R. & Kalodimos, C. G. Protein dynamics and allostery: an NMR view. Curr. Opin. Struct. Biol. 21, 62 67 (2011) 21. Akke, M., Bruschweiler, R. & Palmer, A. G. I. NMR order parameters and free energy: an analytical approach and its application to cooperative Ca2+ binding b y calbindin D9k. J. Am. Chem. Soc. 115, 9832 9833 (1993) 22. Yang, D. & Kay, L. Contributions to conformational entropy arising from bond

vector fluctuations measured from NMR-derived order parameters: application to protein folding. J. Mol. Biol. 263, 369 382 (1996) 23. Li, Z., Raychaudhuri, S. & Wand, A. J. Insights into the local residual entr opy of proteins provided by NMR relaxation. Protein Sci. 5, 2647 2650 (1996) 24. Frederick, K. K., Marlow, M. S., Valentine, K. G. & Wand, A. J. Conformation al entropy in molecular recognition by proteins. Nature 448, 325 329 (2007) 25. Marlow, M. S., Dogan, J., Frederick, K. K., Valentine, K. G. & Wand, A. J. T he role of conformational entropy in molecular recognition by calmodulin. Nature Chem. Biol. 6, 352 358 (2010) 26. Petit, C. M., Zhang, J., Sapienza, P. J., Fuentes, E. J. & Lee, A. L. Hidden dynamic allostery in a PDZ domain. Proc. Natl Acad. Sci. USA 106, 18249 18254 (20 09) 27. Akke, M. Conformational dynamics and thermodynamics of protein-ligand bindin g studied by NMR relaxation. Biochem. Soc. Trans. 40, 419 423 (2012) Rosetta Review For example, the explicit structure of solvent, long-range electrostatics, and r esidual dynamics in the molecule have been ignored. Another striking omission is the massive entropy change of th e molecule upon attaining an ordered structure