A grand challenge of biophysics is to understand protein folding, stability, flexibility, and function in terms of structure and solvent condition. A novel Distance Constraint Model (DCM) is employed to accurately predict protein stability in aqueous solution under specified thermodynamic conditions (i.e. temperature, pH, ionic strength, etc) from known three-dimensional structure. This project builds upon prior success of the PI in developing efficient rigidity-graph algorithms to identify flexible and rigid regions in proteins modeled as a fixed constraint topology, and development of the DCM. The DCM is based on the hypothesis that network rigidity is an underlying mechanism for enthalpy-entropy compensation, yielding a mathematically precise algorithm to account for non-additivity in free energy decompositions. A proof of concept, minimal DCM, will be extended in this project to include explictit modeling of essential entropy-compensation mechanisms that include (a) hydration, (b) hydrophobic interactions, (c) electrostatics interactions, with (d) a residue-specific parameterization. These extensions will allow prediction of protein stability in mixed solvent conditions, and bring the DCM closer to a fully transferable parameterization. However, parameter transferability is not a requirement of this proposed work, as the utility of our minimal DCM has been firmly established. The first outcome.of this work will be the release of a fast computational tool that harmoniously quantifies stabilitiy and flexibility in practical computing times necessary for protien design applications. For example, local- details of protein flexibility are quantified to identify correlated atomic motions important for induced fit of ligand binding and allosteric conformational changes. Synergistic application of the DCM with protein family evolutionary descriptions will provide key insight into familial variability of Quantified Stability/Flexibility Relationships (QSFR). The second outcome will be a public accessible QSFR database providing users wide access to DCM results and analysis tools will give users a practical means to better understand protein function in realistic computing times needed for the post-geonomic era.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM073082-04
Application #
7589702
Study Section
Biodata Management and Analysis Study Section (BDMA)
Program Officer
Wehrle, Janna P
Project Start
2006-03-01
Project End
2012-08-31
Budget Start
2009-03-01
Budget End
2012-08-31
Support Year
4
Fiscal Year
2009
Total Cost
$328,727
Indirect Cost
Name
University of North Carolina Charlotte
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
066300096
City
Charlotte
State
NC
Country
United States
Zip Code
28223
Herring, Charles A; Singer, Christopher M; Ermakova, Elena A et al. (2015) Dynamics and thermodynamic properties of CXCL7 chemokine. Proteins 83:1987-2007
David, Charles C; Jacobs, Donald J (2014) Principal component analysis: a method for determining the essential dynamics of proteins. Methods Mol Biol 1084:193-226
Li, Tong; Verma, Deeptak; Tracka, Malgorzata B et al. (2014) Thermodynamic stability and flexibility characteristics of antibody fragment complexes. Protein Pept Lett 21:752-65
Brown, Matthew C; Verma, Deeptak; Russell, Christian et al. (2014) A case study comparing quantitative stability-flexibility relationships across five metallo-?-lactamases highlighting differences within NDM-1. Methods Mol Biol 1084:227-38
Verma, Deeptak; Guo, Jun-Tao; Jacobs, Donald J et al. (2014) Towards comprehensive analysis of protein family quantitative stability-flexibility relationships using homology models. Methods Mol Biol 1084:239-54
Verma, Deeptak; Jacobs, Donald J; Livesay, Dennis R (2013) Variations within class-A ?-lactamase physiochemical properties reflect evolutionary and environmental patterns, but not antibiotic specificity. PLoS Comput Biol 9:e1003155
Trivedi, Darshan V; David, Charles; Jacobs, Donald J et al. (2012) Switch II mutants reveal coupling between the nucleotide- and actin-binding regions in myosin V. Biophys J 102:2545-55
Gonzalez, Luis C; Wang, Hui; Livesay, Dennis R et al. (2012) Calculating ensemble averaged descriptions of protein rigidity without sampling. PLoS One 7:e29176
Jacobs, Donald J; Livesay, Dennis R; Mottonen, James M et al. (2012) Ensemble properties of network rigidity reveal allosteric mechanisms. Methods Mol Biol 796:279-304
David, Charles C; Jacobs, Donald J (2011) Characterizing protein motions from structure. J Mol Graph Model 31:41-56

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