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 can not 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 specific aims of this application are 1) to advance atomic-level studies of pH-dependent phenomena by further developing continuous constant pH molecular dynamics and related methodologies, and 2) to 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-, thermo- and hyperthermophilic variants of peripheral subunit binding domain. The proposed method development will provide the 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

We plan to develop new simulation techniques, theoretical approaches and experimental strategies to significantly advance the state of the art in the study of electrostatic phenomena in biology. By exploiting a novel set of methods, approaches and tools that the PI has developed and will continue to develop in this application, we seek to shift the native-centric paradigm of protein stability and function, and transform the static-structure based view of protein electrostatics.

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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Wehrle, Janna P
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University of Maryland Baltimore
Schools of Pharmacy
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Ellis, Christopher R; Tsai, Cheng-Chieh; Hou, Xinjun et al. (2016) Constant pH Molecular Dynamics Reveals pH-Modulated Binding of Two Small-Molecule BACE1 Inhibitors. J Phys Chem Lett 7:944-9
Huang, Yandong; Chen, Wei; Dotson, David L et al. (2016) Mechanism of pH-dependent activation of the sodium-proton antiporter NhaA. Nat Commun 7:12940
Ellis, Christopher R; Shen, Jana (2015) pH-Dependent Population Shift Regulates BACE1 Activity and Inhibition. J Am Chem Soc 137:9543-6
Morrow, Brian H; Payne, Gregory F; Shen, Jana (2015) pH-Responsive Self-Assembly of Polysaccharide through a Rugged Energy Landscape. J Am Chem Soc 137:13024-30
Chen, Wei; Shi, Chuanyin; Shen, Jana (2015) Nascent β-Hairpin Formation of a Natively Unfolded Peptide Reveals the Role of Hydrophobic Contacts. Biophys J 109:630-8
Chen, Wei; Shi, Chuanyin; MacKerell Jr, Alexander D et al. (2015) Conformational Dynamics of Two Natively Unfolded Fragment Peptides: Comparison of the AMBER and CHARMM Force Fields. J Phys Chem B 119:7902-10
Chen, Wei; Shen, Jana K (2014) Effects of system net charge and electrostatic truncation on all-atom constant pH molecular dynamics. J Comput Chem 35:1986-96
Chen, Wei; Morrow, Brian H; Shi, Chuanyin et al. (2014) Recent development and application of constant pH molecular dynamics. Mol Simul 40:830-838
Cote, Yoann; Fu, Iris W; Dobson, Eric T et al. (2014) Mechanism of the pH-Controlled Self-Assembly of Nanofibers from Peptide Amphiphiles. J Phys Chem C Nanomater Interfaces 118:16272-16278
Morrow, Brian H; Eike, David M; Murch, Bruce P et al. (2014) Predicting proton titration in cationic micelle and bilayer environments. J Chem Phys 141:084714

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