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Electrostatic modulation of protein stability and folding

蛋白质稳定性和折叠的静电调节

基本信息

批准号：
8706903
负责人：
Jana Shen
金额：
$ 29.17万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706903
关键词：
Address Benchmarking Binding Biological Models Biological Process Biology Catalysis Charge Communities Computer software Computing Methodologies Coupled Data Development Disease Electrostatics Environment Goals Homologous Gene Hybrids Ions Knowledge Leucine Zippers Measurement Methodology Methods N-terminal Nature Peptide Fragments Peripheral Postdoctoral Fellow Protein Engineering Proteins Protocols documentation Protons Psychological Techniques Qualifying Research Residual state Role Scheme Sodium Chloride Solvents Structure Study models Surface Techniques Testing Theoretical Studies Titrations Validation Variant Work base computer cluster computing resources design driving force graduate student improved insight method development molecular dynamics novel novel strategies post-doctoral training protein folding research study response ribosomal protein L9 simulation theories tool villin

项目摘要

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.

静电现象在蛋白质折叠、结合等生物过程中普遍存在