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)
Research Project (R01)
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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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Liu, Zhenxing; Thirumalai, D (2018) Denaturants Alter the Flux through Multiple Pathways in the Folding of PDZ Domain. J Phys Chem B 122:1408-1416
Toan, Ngo Minh; Thirumalai, D (2018) Forced-rupture of cell-adhesion complexes reveals abrupt switch between two brittle states. J Chem Phys 148:123332
Litvinov, Rustem I; Kononova, Olga; Zhmurov, Artem et al. (2018) Regulatory element in fibrin triggers tension-activated transition from catch to slip bonds. Proc Natl Acad Sci U S A 115:8575-8580
Chakrabarti, Shaon; Hinczewski, Michael; Thirumalai, D (2017) Phenomenological and microscopic theories for catch bonds. J Struct Biol 197:50-56
Zhuravlev, Pavel I; Hinczewski, Michael; Chakrabarti, Shaon et al. (2016) Force-dependent switch in protein unfolding pathways and transition-state movements. Proc Natl Acad Sci U S A 113:E715-24
Hori, Naoto; Denesyuk, Natalia A; Thirumalai, D (2016) Salt Effects on the Thermodynamics of a Frameshifting RNA Pseudoknot under Tension. J Mol Biol 428:2847-59
Lin, Jong-Chin; Yoon, Jeseong; Hyeon, Changbong et al. (2015) Using simulations and kinetic network models to reveal the dynamics and functions of riboswitches. Methods Enzymol 553:235-58
Guinn, Emily J; Jagannathan, Bharat; Marqusee, Susan (2015) Single-molecule chemo-mechanical unfolding reveals multiple transition state barriers in a small single-domain protein. Nat Commun 6:6861
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
Hyeon, Changbong; Hinczewski, Michael; Thirumalai, D (2014) Evidence of disorder in biological molecules from single molecule pulling experiments. Phys Rev Lett 112:138101

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