A molecular understanding of the way proteins and RNA fold and how they respond to each other holds the key to describing their functions and the ability to design biological molecules with novel functions. Spectacular advances in experiments, that manipulate biomolecules at the single molecule level using mechanical force, are providing an unprecedented picture of the folding landscapes of proteins, RNA, and ligand-protein complexes. Computer simulations that can be done under conditions that are similar to those used in experiments are required to extract molecular details of the underlying biophysical processes from measurements. We describe novel theoretical and computational tools that are not only integral to the understanding of the experiments but are also useful in predicting their outcomes over a range of conditions that are difficult to explore in the laboratory. Using computational methods, we are poised to make substantial progress in quantitatively describing the folding mechanisms of proteins and RNA and the interactions between cell adhesion molecules and their cognate ligands. In particular, the proposed research will offer insights into the molecular basis of elasticity of Green Fluorescent Protein and Lysozyme and the dependence of folding routes in RNA and proteins on the precise way force is applied. Applications are also planned to explore mechanical stability of Ubiquitin in the presence of crowding particles. The work on the response of the complex between the cell adhesion molecule PSelectin and the ligand is intended to provide molecular details of the unusual enhancement of the lifetime of the complex at low forces. Our studies will lead to a global framework for interpreting a wide range of single molecule experiments and will prove essential in the design of new experiments that can probe biophysical processes under cellular conditions. The conceptual progress and applications to a number of cutting edge problems that is expected from the proposed researches will lead to a substantial advance in our understanding of the response of biological molecules to force - which is pivotal to a number of in vitro and in vivo problems.

Public Health Relevance

Understanding how RNA and proteins fold and interact with each other holds the key to describing their functions. The proposed research will give a molecular view of the underlying mechanisms of these processes at the single molecule level. The studies will give us insights into diseases linked to misfolding and the biophysical basis of response of cell adhesion proteins to inflammation and tissue injury.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Brazhnik, Paul
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University of Maryland College Park
Other Basic Sciences
Schools of Arts and Sciences
College Park
United States
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Chakrabarti, Shaon; Hinczewski, Michael; Thirumalai, D (2014) Plasticity of hydrogen bond networks regulates mechanochemistry of cell adhesion complexes. Proc Natl Acad Sci U S A 111:9048-53
Ramm, Beatrice; Stigler, Johannes; Hinczewski, Michael et al. (2014) Sequence-resolved free energy profiles of stress-bearing vimentin intermediate filaments. Proc Natl Acad Sci U S A 111:11359-64
Zhuravlev, Pavel I; Reddy, Govardhan; Straub, John E et al. (2014) Propensity to form amyloid fibrils is encoded as excitations in the free energy landscape of monomeric proteins. J Mol Biol 426:2653-66
Hyeon, Changbong; Hinczewski, Michael; Thirumalai, D (2014) Evidence of disorder in biological molecules from single molecule pulling experiments. Phys Rev Lett 112:138101
Samanta, Himadri S; Thirumalai, D (2013) Exact solution of the Zwanzig-Lauritzen model of polymer crystallization under tension. J Chem Phys 138:104901
Thirumalai, D; Liu, Zhenxing; O'Brien, Edward P et al. (2013) Protein folding: from theory to practice. Curr Opin Struct Biol 23:22-9
Chen, Jie; Thirumalai, D (2013) Helices 2 and 3 are the initiation sites in the PrP(C) ýýý PrP(SC) transition. Biochemistry 52:310-9
Pincus, David L; Thirumalai, D (2013) Force-induced unzipping transitions in an athermal crowded environment. J Phys Chem B 117:13107-14
Hinczewski, Michael; Tehver, Riina; Thirumalai, D (2013) Design principles governing the motility of myosin V. Proc Natl Acad Sci U S A 110:E4059-68
Hinczewski, Michael; Gebhardt, J Christof M; Rief, Matthias et al. (2013) From mechanical folding trajectories to intrinsic energy landscapes of biopolymers. Proc Natl Acad Sci U S A 110:4500-5

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