权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Elucidating Angular Protein Motion using Kinetic Ensemble Refinement

使用动力学系综细化阐明角蛋白运动

基本信息

批准号：
10203376
负责人：
Colin Alexander Smith
金额：
$ 48.37万
依托单位：
WESLEYAN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10203376
关键词：
Accounting Active Sites Address Adoption Advanced Development Affect Algorithms Allosteric Regulation Amino Acids Benchmarking Binding Sites Biology Biophysical Process Biophysics Catalysis Chemicals Computational Technique Computer Models Computer software Cryoelectron Microscopy Crystallization Cyclophilin A Data Development Enzymes Exhibits Foundations Goals Individual Kinetics Knowledge Life Ligand Binding Measures Methodology Methods Modeling Molecular Motion Movement Mutagenesis Nuclear Nuclear Magnetic Resonance Nucleic Acid Regulatory Sequences Pharmaceutical Preparations Physics Positioning Attribute Process Protein Dynamics Proteins Protocols documentation Public Health Research Side Structure Techniques Temperature Testing Therapeutic Translating Uncertainty Validation Vertebral column Work X-Ray Crystallography active method base care outcomes crystallinity design drug development exhaustion expectation experimental study improved molecular modeling multi-scale modeling novel strategies novel therapeutics nuclear Overhauser enhancement programs protein function protein structure restraint structural biology tool

项目摘要

PROJECT SUMMARY/ABSTRACT To advance the understanding of atomic-level mechanisms behind critical protein functions like enzyme catalysis and allosteric regulation, it is important to first elucidate a true representation of the protein in solution. In an effort to achieve this long term goal, we will use the recently developed Kinetic Ensemble approach to transform the way in which nuclear magnetic resonance (NMR) data is computationally modeled to solve protein structures and measure protein motions. NMR is one of the most powerful techniques for elucidating the structure and dynamics of proteins. It enables their study in solution (unlike x-ray crystallography) and can capture critical structural rearrangements as they happen at room temperature (unlike cryo-electron microscopy). However, despite these advantages, there have been relatively few practical improvements to one of the foundational aspects behind the way protein structures are solved, namely the calculation of interatomic distances from nuclear Overhauser effect (NOE) experiments. Such methods have remained largely qualitative, resulting in large uncertainties in the atomic positions for most NMR structures. Also, the field has almost completely ignored how angular motion and kinetics affect the NOE, resulting in atoms appearing much further away from one another than they actually are. To overcome these significant deficiencies, we will implement and test new Kinetic Ensemble-based refinement algorithms that are considerably more accurate and physically realistic than previous approaches, accounting for both angular motion and kinetics. To eliminate a significant fraction of the systematic and random structural errors resulting from poorly quantified NMR spectra, we will also integrate advances made by the FitNMR peak quantification software recently developed by our lab. These methods will be used to create better experimental NMR structures, more exhaustive models of side chain dynamics, and determine differences between solution and crystal states with unprecedented detail. This work will allow much more accurate determination of the structural dynamics in parts of the protein exhibiting significant fluctuations, including protein active sites, regulatory regions, and hidden binding sites. Such knowledge will advance our fundamental understanding of protein biophysics and facilitate rational design of new therapeutics.

项目总结/文摘