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.
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.
|Lipska, Agnieszka G; Seidman, Steven R; Sieradzan, Adam K et al. (2016) Molecular dynamics of protein A and a WW domain with a united-residue model including hydrodynamic interaction. J Chem Phys 144:184110|
|Krupa, PaweÅ‚; Mozolewska, Magdalena A; WiÅ›niewska, 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|
|WiÅ›niewska, Marta; Sobolewski, Emil; OÅ‚dziej, StanisÅ‚aw 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, PaweÅ‚; 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|
|GoÅ‚aÅ›, 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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