The overall objective of this laboratory is to solve the problem of how proteins fold into their native conformations. For this purpose, use is made of the methodology of protein chemistry, and experimental and theoretical techniques are being developed and applied to provide an understanding of the internal interactions that stabilize native proteins in aqueous solution. This project is concerned with the theoretical work, which involves the use of empirical potentials (including the effects of hydration and entropy) in various computational approaches to study the interactions in protein folding. Emphasis is currently being placed on solving the multiple-minima problem arising from the existence of numerous local minima in the potential energy surface of the protein, the objective being to locate the global minimum on this surface. The methods developed to solve this problem are also being applied to two global optimization problems in crystallography (prediction of crystal structures and surmounting the phase problem in X-ray crystallography). An understanding of the interaction in proteins is of potential applicability to the elucidation of the role of conformation in biological processes; e.g., the undesirable association of sickle-cell hemoglobin or the induction of an oncogene product whose properties involve a conformational change when only one amino acid residue in the sequence is changed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM014312-43
Application #
2900452
Study Section
Special Emphasis Panel (ZRG3-BBCA (03))
Project Start
1977-01-01
Project End
2002-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
43
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Ithaca
State
NY
Country
United States
Zip Code
14850
Cote, Yoann; Delarue, Patrice; Scheraga, Harold A et al. (2018) From a Highly Disordered to a Metastable State: Uncovering Insights of ?-Synuclein. ACS Chem Neurosci 9:1051-1065
Vorobjev, Yury N; Scheraga, Harold A; Vila, Jorge A (2018) A comprehensive analysis of the computed tautomer fractions of the imidazole ring of histidines in Loligo vulgaris. J Biomol Struct Dyn 36:3094-3105
Grassein, Paul; Delarue, Patrice; Scheraga, Harold A et al. (2018) Statistical Model To Decipher Protein Folding/Unfolding at a Local Scale. J Phys Chem B 122:3540-3549
Solé-Domènech, Santiago; Rojas, Ana V; Maisuradze, Gia G et al. (2018) Lysosomal enzyme tripeptidyl peptidase 1 destabilizes fibrillar A? by multiple endoproteolytic cleavages within the ?-sheet domain. Proc Natl Acad Sci U S A 115:1493-1498
Vorobjev, Yury N; Scheraga, Harold A; Vila, Jorge A (2018) Coupled molecular dynamics and continuum electrostatic method to compute the ionization pKa's of proteins as a function of pH. Test on a large set of proteins. J Biomol Struct Dyn 36:561-574
Keasar, Chen; McGuffin, Liam J; Wallner, Björn et al. (2018) An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12. Sci Rep 8:9939
Rojas, Ana; Maisuradze, Nika; Kachlishvili, Khatuna et al. (2017) Elucidating Important Sites and the Mechanism for Amyloid Fibril Formation by Coarse-Grained Molecular Dynamics. ACS Chem Neurosci 8:201-209
He, Yi; Maisuradze, Gia G; Yin, Yanping et al. (2017) Sequence-, structure-, and dynamics-based comparisons of structurally homologous CheY-like proteins. Proc Natl Acad Sci U S A 114:1578-1583
Makowski, Mariusz; Liwo, Adam; Scheraga, Harold A (2017) Simple Physics-Based Analytical Formulas for the Potentials of Mean Force of the Interaction of Amino Acid Side Chains in Water. VII. Charged-Hydrophobic/Polar and Polar-Hydrophobic/Polar Side Chains. J Phys Chem B 121:379-390
Vila, Jorge A; Scheraga, Harold A (2017) Limiting Values of the one-bond C-H Spin-Spin Coupling Constants of the Imidazole Ring of Histidine at High-pH. J Mol Struct 1134:576-581

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