Structural and Mechanistic Studies of Essential Microbial Kinases

必需微生物激酶的结构和机制研究

• 批准号: 8465596
• 负责人: Paul Abell Sims
• 金额: $ 21.94万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465596
• 关键词: Address; Benchmarking; Binding; Biological Models; Biological Process; Biology; Catalysis; Centers of Research Excellence; Charge; Communities; Computing Methodologies; Data; Development; Disease; Electrostatics; Environment; Enzymes; Goals; Homologous Gene; Instruction; Ions; Knowledge; Leucine Zippers; Measurement; Methodology; Methods; Modeling; N-terminal; Nature; Oklahoma; Peptide Fragments; Peripheral; Postdoctoral Fellow; Protein Engineering; Proteins; Protocols documentation; Psychological Techniques; Qualifying; Regulation; Research; Residual state; Role; Sampling; Sodium Chloride; Solvents; Structure; Supercomputing; Surface; Techniques; Testing; Theoretical Studies; Titrations; Validation; Variant; Work; antigen antibody binding; base; computer cluster; computing resources; design; driving force; graduate student; improved; inhibitor/antagonist; insight; method development; molecular dynamics; novel strategies; post-doctoral training; protein folding; protonation; research study; response; ribosomal protein L9; simulation; structural biology; theories; thermostability; tool; villin

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.

静电现象在蛋白质折叠、结合等生物过程中普遍存在