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Computational Studies of Model Systems for Protein Unfolded States

蛋白质未折叠状态模型系统的计算研究

基本信息

批准号：
7588900
负责人：
CARLOS SIMMERLING
金额：
$ 22.62万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-06-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7588900
关键词：
Address Adopted Affect Alanine Algorithms Amber Area Biological Models Boxing Chemicals Collaborations Communities Complex Coupled Couples Data Development Disease Elements Entropy Equation Event Experimental Models Feedback Free Energy Generations Glycine Human Hybrids Hydrogen Bonding Hydrophobic Interactions Investigation Ions Joints Kinetics Measurement Measures Methods Modeling Molecular Conformation Mutation Nature Peptides Performance Phase Physiological Plant Roots Population Principal Investigator Proline Property Proteins Publishing Research Research Personnel Residual state Resolution Role Sampling Simulate Solvents Specific qualifier value Speed Structure Study models System Techniques Temperature Testing Thermodynamics Time Validation Vertebral column Weight Work alanylproline base chemical stability computer studies cost flexibility improved insight meetings mutant novel novel strategies particle polypeptide programs prolylglycine protein folding research study simulation single molecule success theories tool

项目摘要

While unfolded states of proteins were previously thought to be largely random, evidence of specific structure is accumulating. Even at low populations this type of ordering could have direct bearing on protein stability, folding mechanism, and rate, as well as the misfolding and aggregation that are implicated in many human disorders. In most cases, the weak nature of the residual structure and low populations of misfolded states under physiological conditions preclude direct and detailed characterization of these ensembles using experimental techniques. Simulations have begun to provide data complementary to experiments, since they can provide structural detail with single molecule resolution on a time scale inaccessible to most experiments. However, simulations fail in many important cases for multiple reasons. This proposal outlines continued development of simulation algorithms and force fields to enable successful application to the study of unfolded states, with direct validation against experimental data obtained through established collaborations. A strong emphasis is placed on conformational sampling; a major component of the project involves development of a novel sampling approach that provides improved convergence of ensemble data with explicit inclusion of solvent at a significantly reduced computational cost. Simulations will be performed on several model systems of varying complexity. In each case, specific mutations will probe interactions that are hypothesized to be involved in determining the structure or stability of the native fold. Other mutants probe the effect on stability of interactions that we have observed in the unfolded state. These studies will provide useful insight into these important model systems, and will also provide valuable and critical feedback on the performance of our force fields and sampling methods. The next phase of the research involves characterization of unfolded ensembles for each model system, and generation of experimentally testable hypotheses about the nature of any residual structure. For each of the model systems, recent experiments suggest that residual structure may exist in the unfolded state, and our simulations will provide important models for interpretation of this data. Additional studies of the unfolded state and the role of entropy in folding will be performedthrough replacement of flexible glycine and rigid proline with alanine, investigating the effect on unfolded state entropy and free energy of folding.

虽然以前认为蛋白质的未折叠状态在很大程度上是随机的，但有证据表明，它们具有特异性