The goal of the proposed work is the development of statistical mechanical models designed to disect the nature and relative importance of short, medium and long range interactions and topological constraints on the folding transition of predominantly alpha-helical proteins. Initially the proposed work focuses on the further development of the equilibrium and kinetic theory of the helix-coil transition in alpha-helical, two-chain, coiled coils such as the important muscle regulatory protein tropomyosin. These architecturally simple systems are not only of great intrinsic Biochemical interest (e.g. tropomyosin plays an important role in muscle contraction) but also possess many qualitative aspects of the globular protein folding process; insights gained from these studies will be employed to examine the folding transition in globular proteins. Specifically, the proposed work on coiled coils and globular protein models comprises the following (1) the further development and application of the equilibrium theory of the helix-coil transition in coiled coils to provide a semi- quantitative theory of all extant experimental data on noncrosslinked, singly and doubly crosslinked rabbit alpha-and beta-tropomyosin. (2) The investigation of the effect of crosslink induced stress on the coiled coil structure through the construction of tropomyosin fragments using the ECEPP/2 procedure of Scheraga et al., followed by potential energy minimization. (3) Employing dynamic Monte Carlo simulations and analytic models, the kinetic theory of the coiled coil helix-to- random coil transition will be extended to include loop entropy (the reduction in configurational entropy when the ends of a random coil are constrained relative to when they are free, an effect of crucial importance at equilibrium) and for noncrosslinked molecules, chain dissociation an interchange between the out-of-register states of the two chains. Attempts will be made to identify experimental signatures indicative of the presence of the various relaxation mechanisms. (4) An equilibrium and kinetic theory of the native to denatured transition in model globular proteins composed of multiply interacting helices joined together by loops or bends will be developed. These studies are designed to test the conjectures that loop entropy is largely responsible for the validity of the equilibrium two state model of single domain globular protein folding and for the kinetic stabilization of the native state. (5) To elucidate plausible nascent folding pathways, Brownian dynamics simulations of schematic models are proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
7R01GM037408-04
Application #
3292705
Study Section
Biophysics and Biophysical Chemistry A Study Section (BBCA)
Project Start
1989-07-01
Project End
1989-11-30
Budget Start
1989-07-01
Budget End
1989-11-30
Support Year
4
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
Zhou, Hongyi; Gao, Mu; Skolnick, Jeffrey (2016) ENTPRISE: An Algorithm for Predicting Human Disease-Associated Amino Acid Substitutions from Sequence Entropy and Predicted Protein Structures. PLoS One 11:e0150965
Zhou, Hongyi; Gao, Mu; Skolnick, Jeffrey (2015) Comprehensive prediction of drug-protein interactions and side effects for the human proteome. Sci Rep 5:11090
Skolnick, Jeffrey; Gao, Mu; Roy, Ambrish et al. (2015) Implications of the small number of distinct ligand binding pockets in proteins for drug discovery, evolution and biochemical function. Bioorg Med Chem Lett 25:1163-70
Srinivasan, Bharath; Skolnick, Jeffrey (2015) Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors. FEBS J 282:1922-38
Tonddast-Navaei, Sam; Skolnick, Jeffrey (2015) Are protein-protein interfaces special regions on a protein's surface? J Chem Phys 143:243149
Srinivasan, Bharath; Tonddast-Navaei, Sam; Skolnick, Jeffrey (2015) Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase. Eur J Med Chem 103:600-14
Boles, Richard G; Hornung, Holly A; Moody, Alastair E et al. (2015) Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic ""functional"" symptomatology including pain, fatigue and gastrointestinal dysmotility. Mitochondrion 23:64-70
Gao, Mu; Zhou, Hongyi; Skolnick, Jeffrey (2015) Insights into Disease-Associated Mutations in the Human Proteome through Protein Structural Analysis. Structure 23:1362-9
Roy, Ambrish; Srinivasan, Bharath; Skolnick, Jeffrey (2015) PoLi: A Virtual Screening Pipeline Based on Template Pocket and Ligand Similarity. J Chem Inf Model 55:1757-70
Roy, Ambrish; Skolnick, Jeffrey (2015) LIGSIFT: an open-source tool for ligand structural alignment and virtual screening. Bioinformatics 31:539-44

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