Electrostatic phenomena are ubiquitous in biological processes such as protein folding, binding, and catalysis. Our current knowledge of electrostatic effects on protein stability is mainly derived from protein engineering experiments and theoretical studies using static-structure based Poisson-Boltzmann calculations. However, while macroscopic measurements often cannot isolate electrostatic effects from others, the accuracy of theoretical predictions is limited by the lack of explicit treatment of protein dielectric response, conformational dynamics and effects due to residual structures in the unfolded state. As a result, despite two decades of research, important questions such as how and to what extent electrostatic interactions modulate protein stability have not been adequately answered. The lack of accurate means to predict electrostatic contributions not only hampers fundamental understanding of protein stability but also poses a roadblock for advancing computational protein design. The objectives of this application are to 1) advance atomic-level studies of pH-dependent phenomena by further developing continuous constant pH molecular dynamics and related methodologies, and 2) improve quantitative prediction and detailed understanding of electrostatic modulation of protein stability by studying several model systems including the N-terminal domain of ribosomal L9 protein, villin headpiece subdomain, leucine zipper, and meso-, thermoand hyper thermophilic variants of peripheral subunit binding domain. The proposed method development will provide the structural biology community with powerful tools for studying a wide range of electrostatic phenomena in biology. The insights gained in the application studies are expected to shift the native-centric paradigm of protein stability and function and transform the static-structure based view of protein electrostatics. They will also help establish general principles for computational protein design.

Public Health Relevance

This research will provide important insight into biological processes such as regulation of protein folding, thermostability, protein-inhibitor binding, antibody-antigen recognition, and enzyme catalysis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
5P20GM103640-03
Application #
8666008
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
3
Fiscal Year
2014
Total Cost
$219,419
Indirect Cost
$71,219
Name
University of Oklahoma Norman
Department
Type
DUNS #
848348348
City
Norman
State
OK
Country
United States
Zip Code
73019
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