The main problem of protein folding is the """"""""exponential search"""""""" (or multiple minimum) problem. To find the unique native structure (at the global minimum of free energy) requires a search over the whole conformational space, the size of which increases exponentially with chain length. But proteins fold much faster than this. How can a protein find the global optimum without a globally exhaustive search? We will address this question using a 2-dimensional short-chain HP (hydrophobic/polar) copolymer lattice model. This appears to be the simplest physical model of protein stability and structure that is amenable to rigorous study. It has been shown to mimic many aspects of protein behavior. Most importantly, the model has the same exponential search problem that real proteins have. We are exploring: (i) how the shape of a conformational space is determined by its amino acid sequence, (ii) the kinetic barriers to folding using Monte Carlo lattice kinetics and an analytical transition matrix approach, and (iii) distance measures that define structural similarities in real proteins and lattice models; these are necessary to define """"""""nearness"""""""" to the native structure and """"""""folding pathways."""""""" We have very exciting preliminary results suggesting that an answer to the search puzzle for the model may be near at hand. We find that some sequences fold faster than others, distinguished by characteristically shaped conformational spaces. We are finding some families of sequences that fold faster than exponentially and we have a preliminary algorithm that finds, for such sequences, the unique native lattice conformation and other deep minima without exhaustive search. We expect this model study to have significant implications for principles and algorithms of protein folding.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM034993-14
Application #
6179736
Study Section
Molecular and Cellular Biophysics Study Section (BBCA)
Program Officer
Flicker, Paula F
Project Start
1985-09-12
Project End
2001-12-09
Budget Start
2000-05-01
Budget End
2001-12-09
Support Year
14
Fiscal Year
2000
Total Cost
$178,811
Indirect Cost
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Perez, Alberto; MacCallum, Justin L; Brini, Emiliano et al. (2015) Grid-based backbone correction to the ff12SB protein force field for implicit-solvent simulations. J Chem Theory Comput 11:4770-9
Pressé, Steve; Peterson, Jack; Lee, Julian et al. (2014) Single molecule conformational memory extraction: p5ab RNA hairpin. J Phys Chem B 118:6597-603
Roy, Arijit; Perez, Alberto; Dill, Ken A et al. (2014) Computing the relative stabilities and the per-residue components in protein conformational changes. Structure 22:168-75
Presse, Steve; Lee, Julian; Dill, Ken A (2013) Extracting conformational memory from single-molecule kinetic data. J Phys Chem B 117:495-502
Peterson, G Jack; Pressé, Steve; Peterson, Kristin S et al. (2012) Simulated evolution of protein-protein interaction networks with realistic topology. PLoS One 7:e39052
Schmit, Jeremy D; Dill, Ken (2012) Growth rates of protein crystals. J Am Chem Soc 134:3934-7
Dill, Ken A; MacCallum, Justin L (2012) The protein-folding problem, 50 years on. Science 338:1042-6
Perez, Alberto; Yang, Zheng; Bahar, Ivet et al. (2012) FlexE: Using elastic network models to compare models of protein structure. J Chem Theory Comput 8:3985-3991
Ge, Hao; Presse, Steve; Ghosh, Kingshuk et al. (2012) Markov processes follow from the principle of maximum caliber. J Chem Phys 136:064108
MacCallum, Justin L; Pérez, Alberto; Schnieders, Michael J et al. (2011) Assessment of protein structure refinement in CASP9. Proteins 79 Suppl 10:74-90

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