Skip directly to content

Minimize RSR Award Detail

Research Spending & Results

Award Detail

Doing Business As Name:University of Maryland College Park
  • Devarajan Thirumalai
  • (512) 471-2979
Award Date:09/02/2009
Estimated Total Award Amount: $ 1,369,898
Funds Obligated to Date: $ 1,369,898
  • FY 2009=$260,000
  • FY 2013=$287,528
  • FY 2010=$543,590
  • FY 2012=$278,780
Start Date:09/01/2009
End Date:08/31/2014
Transaction Type:Grant
Awarding Agency Code:4900
Funding Agency Code:4900
CFDA Number:47.049
Primary Program Source:040100 NSF RESEARCH & RELATED ACTIVIT
Award Title or Description:Topics in Protein Folding and Dynamics
Federal Award ID Number:0910433
DUNS ID:790934285
Parent DUNS ID:003256088
Program Officer:
  • Evelyn Goldfield
  • (703) 292-2173

Awardee Location

Street:3112 LEE BLDG 7809 Regents Drive
County:College Park
Awardee Cong. District:05

Primary Place of Performance

Organization Name:University of Maryland College Park
Street:3112 LEE BLDG 7809 Regents Drive
County:College Park
Cong. District:05

Abstract at Time of Award

Devarajan Thirumalai of the University of Maryland is supported by an award from the Theoretical and Computational Chemistry division for studies that discover new principles governing the folding of larger proteins under conditions that more closely mimic the cellular environment. These studies span a wide range of scales, from the single molecule to chaperone-assisted rescue of substrate proteins. Particular problems include 1) understanding single molecule spectroscopy; 2) examining folding and kinetics of peptides under confinement, 3) modeling the effects of crowding on protein folding and 4) simulating chaperonin-assisted folding. In order to solve these problems Thirumalai uses a variety of theoretical and computational methods. They include ideas from statistical mechanics, principles of polymer and colloid science, and novel simulation methods. This research is addressing one of the central challenges of modern biology: to understand the physics and dynamics of large molecules such as proteins in a living cell. Thirumalai's work is expected to provide a conceptual framework for understanding how proteins fold. The outcome of the researches will set the stage for providing a quantitative and integrated picture of folding and dynamics with potential applications to a number of other topics including protein-protein and protein-RNA association. This project is supported by the Theoretical and Computational Chemistry Program in a co-funding arrangement with the Molecular Biophysics Program and with the Physics of Living Systems Program.

Publications Produced as a Result of this Research

Note: When clicking on a Digital Object Identifier (DOI) number, you will be taken to an external site maintained by the publisher. Some full text articles may not yet be available without a charge during the embargo (administrative interval).

Some links on this page may take you to non-federal websites. Their policies may differ from this site.

M. Gruebele and D. Thirumalai "Reaches of Chemical Physics in Biology" J. Chem. Phys., v.139, 2013, p.121701.

J. E. Straub and D. Thirumalai "Membrane-protein interactions are key to understanding Amyloid formation" J. Phys. Chem. Lett., v.5, 2014, p.633.

U.D. Priyakumar, C. Hyeon, D. Thirumalai, A.D. MacKerell "Urea Destabilizes RNA by Forming Stacking Interactions and Multiple Hydrogen Bonds with Nucleic Acid Bases" J. Am. Chem. Soc, v.131, 2009, p.17759.

C. Hyeon and D. Thirumalai "Generalized Iterative Annealing model for RNA chaperones" J. Chem. Phys., v.139, 2013, p.121924.

S. Moghaddam, G. Caliskan, S. Chauhan, C. Hyeon, R.M. Briber, D. Thirumalai, S.A. Woodson "Metal Ion Dependence of Cooperative Collapse Transitions in RNA" J. Mol. Biol., v.393, 2009, p.753.

Z. Liu, G. Reddy, E. P. O'Brien, and D. Thirumalai "Collapse kinetics and chevron plots from simulations of denaturant-dependent folding of globular proteins" Proc. Natl. Acad. Sci., v.108, 2011, p.7787.

A. Kudlay, M. S. Cheung, and D. Thirumalai "In?uence of the Shape of Crowding Particles on the Structural Transitions in a Polymer" J. Phys. Chem. B, v.116, 2012, p.8513-8522.

N. M. Toan and D. thirumalai "Theory of Biopolymer Stretching at High forces" Macromolecules, v.43, 2010, p.4394.

C. Hyeon, G. Morrison, D.L. Pincus, D. Thirumalai "Refolding dynamics of stretched biopolymers upon force quench" Proc. Natl. Acad. Sci., v.106, 2009, p.20288.

M. Hinczewski, R. Tehver, and D. Thirumalai "Design principles governing the motility of Myosin V" Proc. Natl. Acad. Sci., v.110, 2013, p.E4059.

N. A. Denesyuk and D. Thirumalai "Entropic stabilization of folded states of RNA due to macromolecular crowding" Biophysical Review, v.5, 2013, p.225.

R. Tehver and D. thirumalai "Rigor to Post-Rigor Transition in Myosin V: Link between the Dynamics and the Supporting Architecture" Structure, v.18, 2010, p.471.

Z. Zhang and D. Thirumalai "Dissecting the Kinematics of the Kinesin Step" Structure, v.20, 2012, p.628-640.

Z. Liu, G. Reddy, and D. Thirumalai "Theory of the Molecular Transfer Model for Proteins with Applications to the Folding of the src-SH3 Domain" J. Phys. Chem. B, v.116, 2012, p.6707-6716.

J. Yoon, J.-C. Lin, C. Hyeon, and D. Thirumalai "Dynamical transition and heterogeneous dynamics in RNA" J. Phys. Chem. B, v.118, 2014, p.7910.

E. Koculi, S. S. Cho, R. Desai, D. Thirumalai, and S. A. Woodson "Folding path of P5abc RNA involves direct coupling of secondary and tertiary structures" Nuc. Acids. Res., v.40, 2012, p.8011-8020.

L. Domingez, S. C. Meredith, J. E. Straub, and D. Thirumalai "Transmembrane fragment of Amyloid Precursor Proteins depend on membrane curvature" J. Am. Chem. Soc, v.136, 2014, p.854.

Hyeon, C; Thirumalai, D "Capturing the essence of folding and functions of biomolecules using coarse-grained models" NATURE COMMUNICATIONS, v.2, 2011, p.. doi:10.1038/ncomms148  View record at Web of Science

E. Denning, D. thirumalai, and A. D. MacKerell "Protonation of trimethyamine N-oxide (TMAO) is required for stabilization of RNA tertiary structure" Biophys. Chem., v.184, 2013, p.8.

Z. Liu, J. Chen, D. Thirumala "On the accuracy of inferring energetic coupling between distant sites in protein families from evolutionary imprints: Illustrations using lattice model" Proteins: Structure, Function, and Genetics, v.77, 2009, p.823.

H. Kang, T. R. Kirkpatrick, and D. Thirumalai "Manifestation of Random First Order Transition theory in Wigner Glasses" Phys. Rev. E, v.88, 2013, p.042308.

J.-C. Lin and D. Thirumalai "Gene Regulation by Riboswitches with and without Negative Feedback Loop" Biophysical. Journal, v.103, 2012, p.2320-2330.

S.S. Cho, D.L. Pincus, D. Thirumalai "Assembly mechanisms of RNA pseudoknots are determined by the stabilities of constituent secondary structures" Proc. Natl. Acad. Sci., v.106, 2009, p.17349.

M. Hinczewski and D. Thirumalai "Cellular signaling networks function as generalized Weiner-Kolmogorov filters to suppress noise" Phys. Rev. X, v.4, 2014, p.041017.

Changbong Hyeon and D. Thirumalai "Chain Length Determines the Folding Rates of RNA" Biophysical Jurnal, v.102, 2012, p.L11-L13.

Cho, SS; Reddy, G; Straub, JE; Thirumalai, D "Entropic Stabilization of Proteins by TMAO" JOURNAL OF PHYSICAL CHEMISTRY B, v.115, 2011, p.13401. doi:10.1021/jp207289  View record at Web of Science

J. Chen, S. Darst, and D. thirumalai "Promoter melting triggered by bacterial RNA polymerase occurs in three steps" Proc. Natl. Acad. Sci., v.107, 2010, p.12523.

D. Thirumalai, E. P. O'Brien, G. Morrison, and D. Thirumalai "Theoretical Perspectives on Protein folding" Ann. Rev. Biophysics, v.39, 2010, p.159.

G. Reddy, Z. Liu, and D. thirumalai "Denaturant-dependent folding of GFP" Proc. Natl. acad. sci., v.109, 2012, p.17832?38.

Denesyuk, NA; Thirumalai, D "Crowding Promotes the Switch from Hairpin to Pseudoknot Conformation in Human Telomerase RNA" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, v.133, 2011, p.11858. doi:10.1021/ja203512  View record at Web of Science

Project Outcomes Report


This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.

The over arching goal of the work conducted during the funding period was to provide hoe proteins, which are the wok horses performing myriads of functions in cells, adopt three-dimensional structure. It is known that if they do not adopt the shapes needed for function they could aggregate, leading to a number of diseases. We made major advances using theoretical and computational methods to describe their folding and function.  The highlights of our accomplishments are:

1) Protein Folding: For the first time, we were able to create models and use computer simulations to precisely predict how a completely unfolded protein reaches the folded functionally competent state. Our predictions for large proteins such as Green Fluorescent Protein (GFP) quantitatively explained all the known experiments. By understanding this process precisely one can design variants of GFP, which will become increasingly important because these proteins are used as markers to image in detail how cells function.

2) Describing cellular protein folding:  A major gap has existed between folding in the laboratory and how those lessons can be used understand the corresponding processes in cells. It turns out that cells are very crowded containing other proteins, RNA, lipids, and ribosomes. How to describe folding in such a crowded environment has remained a major challenge. We created novel theories to understand how crowding affects folding process. This is a complicated problem and we were able to dissect it into bite size pieces by solving subsets of issues quantitatively. As a result, we have provided major guidance for understanding how proteins even in a cellular environment can facilitate folding. Experimentalists have used these theories in analyzing their data.

3) Chaperones to the rescue: Folding is such a key cellular activity that in cases where this does not occur spontaneously there are helper proteins that assist in folding. The bacterial chaperone, GroEL, has been the most well studied system. It is not possible to understand the mechanism by which GroEL helps proteins fold. We realized that GroEL is a machine that consumes energy (generated by hydrolysis) and gives those proteins, which tend to misfold another chance to fold. In the funding period, we translated this picture into precise model capable of rationalizing all known experiments. This is the first and only theory that can account for how this complex machine works in solving a fundamental cellular problem, which is to help proteins reach their functional state.



Last Modified: 01/05/2015
Modified by: Devarajan Thirumalai

For specific questions or comments about this information including the NSF Project Outcomes Report, contact us.