Our long-term objective is to ascertain how protein conformation plays a role in biological function and in various diseases.
Our specific aims are to finish our development of our physics-based united-residue (UNRES) approach to the protein folding problem, i.e., to compute structure, folding pathways, and thermodynamic and dynamic properties. This involves replacing the last remaining knowledge-based term, corresponding to side chain-side chain interactions, by physics-based terms, extension of UNRES to simulate folding of disulfide-containing proteins, and to treat the lipid-membrane environment. At the all-atom level, we will treat the pH-dependent ionization of side chains (including solvation), and the use of 13C1 chemical shifts in protein-structure simulation. We will continue the development of our UNRES model of nucleic acids (NA-UNRES) and merge UNRES and NA-UNRES into a viable package, which will be provided to the community. We will also continue the developments of sampling techniques and parallelization of UNRES/MD to carry out simulations of very large single-chain and oligomeric proteins and their complexes, and develop tools, based on Principal Component Analysis (PCA) for the analysis of mesoscopic-dynamics trajectories. We will demonstrate how these aims can lead to valid predictions of structures and folding pathways of proteins, and protein-nucleic acid and protein-protein complexes. Our main focus will then involve the application of this methodology to a biological problem: the mechanism of action of the human HSP70 chaperone.

Public Health Relevance

As pointed out in the Project Summary, the long-term objective of this research is to ascertain how protein conformation plays a role in various diseases. Examples of such diseases in which conformation plays a role are sickle cell anemia (1) and amyloid diseases such as Alzheimer's (2) and mad cow disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM014312-56
Application #
8274782
Study Section
Macromolecular Structure and Function D Study Section (MSFD)
Program Officer
Wehrle, Janna P
Project Start
1977-01-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
56
Fiscal Year
2012
Total Cost
$513,448
Indirect Cost
$177,212
Name
Cornell University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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Krupa, Paweł; Mozolewska, Magdalena A; Wiśniewska, Marta et al. (2016) Performance of protein-structure predictions with the physics-based UNRES force field in CASP11. Bioinformatics 32:3270-3278
Yin, Yanping; Sieradzan, Adam K; Liwo, Adam et al. (2015) Physics-Based Potentials for Coarse-Grained Modeling of Protein-DNA Interactions. J Chem Theory Comput 11:1792-808
Wiśniewska, Marta; Sobolewski, Emil; Ołdziej, Stanisław et al. (2015) Theoretical Studies of Interactions between O-Phosphorylated and Standard Amino-Acid Side-Chain Models in Water. J Phys Chem B 119:8526-34
Mozolewska, Magdalena A; Krupa, Paweł; Scheraga, Harold A et al. (2015) Molecular modeling of the binding modes of the iron-sulfur protein to the Jac1 co-chaperone from Saccharomyces cerevisiae by all-atom and coarse-grained approaches. Proteins 83:1414-26
Cote, Yoann; Maisuradze, Gia G; Delarue, Patrice et al. (2015) New Insights into Protein (Un)Folding Dynamics. J Phys Chem Lett 6:1082-6
Rackovsky, S (2015) Nonlinearities in protein space limit the utility of informatics in protein biophysics. Proteins 83:1923-8
Gołaś, Ewa I; Czaplewski, Cezary; Scheraga, Harold A et al. (2015) Common functionally important motions of the nucleotide-binding domain of Hsp70. Proteins 83:282-99
Scheraga, Harold A (2015) My 65 years in protein chemistry. Q Rev Biophys 48:117-77
He, Yi; Liwo, Adam; Scheraga, Harold A (2015) Optimization of a Nucleic Acids united-RESidue 2-Point model (NARES-2P) with a maximum-likelihood approach. J Chem Phys 143:243111

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