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.
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.
|Guillen, Katrin P; Ruben, Eliza A; Virani, Needa et al. (2017) Annexin-directed ?-glucuronidase for the targeted treatment of solid tumors. Protein Eng Des Sel 30:85-94|
|Sundaresan, Ramya; Parameshwaran, Hari Priya; Yogesha, S D et al. (2017) RNA-Independent DNA Cleavage Activities of Cas9 and Cas12a. Cell Rep 21:3728-3739|
|Van Orden, Mason J; Klein, Peter; Babu, Kesavan et al. (2017) Conserved DNA motifs in the type II-A CRISPR leader region. PeerJ 5:e3161|
|Murugan, Karthik; Babu, Kesavan; Sundaresan, Ramya et al. (2017) The Revolution Continues: Newly Discovered Systems Expand the CRISPR-Cas Toolkit. Mol Cell 68:15-25|
|Wang, Bing; Powell, Samantha M; Guan, Ye et al. (2017) Nitrosoamphetamine binding to myoglobin and hemoglobin: Crystal structure of the H64A myoglobin-nitrosoamphetamine adduct. Nitric Oxide 67:26-29|
|Li, Yangxiong; Lavey, Nathan P; Coker, Jesse A et al. (2017) Consequences of Depsipeptide Substitution on the ClpP Activation Activity of Antibacterial Acyldepsipeptides. ACS Med Chem Lett 8:1171-1176|
|Terzyan, Simon S; Cook, Paul F; Heroux, Annie et al. (2017) Structure of 6-diazo-5-oxo-norleucine-bound human gamma-glutamyl transpeptidase 1, a novel mechanism of inactivation. Protein Sci 26:1196-1205|
|Motley, Jeremy L; Stamps, Blake W; Mitchell, Carter A et al. (2017) Opportunistic Sampling of Roadkill as an Entry Point to Accessing Natural Products Assembled by Bacteria Associated with Non-anthropoidal Mammalian Microbiomes. J Nat Prod 80:598-608|
|Mooers, Blaine H M (2016) Simplifying and enhancing the use of PyMOL with horizontal scripts. Protein Sci 25:1873-82|
|Lavey, Nathan P; Coker, Jesse A; Ruben, Eliza A et al. (2016) Sclerotiamide: The First Non-Peptide-Based Natural Product Activator of Bacterial Caseinolytic Protease P. J Nat Prod 79:1193-7|
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