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.
|Go?a?, 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|
|Vila, Jorge A; Arnautova, Yelena A; Martin, Osvaldo A et al. (2014) Are accurate computations of the 13C' shielding feasible at the DFT level of theory? J Comput Chem 35:309-12|
|Liwo, Adam; Baranowski, Maciej; Czaplewski, Cezary et al. (2014) A unified coarse-grained model of biological macromolecules based on mean-field multipole-multipole interactions. J Mol Model 20:2306|
|Khoury, George A; Liwo, Adam; Khatib, Firas et al. (2014) WeFold: a coopetition for protein structure prediction. Proteins 82:1850-68|
|He, Yi; Maciejczyk, Maciej; Oldziej, Stanislaw et al. (2013) Mean-field interactions between nucleic-acid-base dipoles can drive the formation of a double helix. Phys Rev Lett 110:098101|
|Krupa, Pawel; Sieradzan, Adam K; Rackovsky, S et al. (2013) Improvement of the treatment of loop structures in the UNRES force field by inclusion of coupling between backbone- and side-chain-local conformational states. J Chem Theory Comput 9:|
|Maisuradze, Gia G; Liwo, Adam; Senet, Patrick et al. (2013) Local vs global motions in protein folding. J Chem Theory Comput 9:2907-2921|
|Makowska, Joanna; Liwo, Adam; Zmudzinska, Wioletta et al. (2012) Like-charged residues at the ends of oligoalanine sequences might induce a chain reversal. Biopolymers 97:240-9|
|Gahl, Robert F; Oswald, Robert E; Scheraga, Harold A (2012) Identification of formation of initial native structure in onconase from an unfolded state. Biochemistry 51:521-32|
|Rojas, Ana V; Liwo, Adam; Scheraga, Harold A (2011) A study of the ?-helical intermediate preceding the aggregation of the amino-terminal fragment of the ? amyloid peptide (A?(1-28)). J Phys Chem B 115:12978-83|
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