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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function D Study Section (MSFD)
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Wehrle, Janna P
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Cornell University
Schools of Arts and Sciences
United States
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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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