PROTEIN STABILITY THEORY

蛋白质稳定性理论

• 批准号: 3306064
• 负责人: Ken A Dill
• 金额: $ 13.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 1995-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3306064
• 关键词: acidity /alkalinity; chemical aggregate; chemical kinetics; chemical stability; computer simulation; conformation; disulfide bond; intermolecular interaction; ionic bond; ionic strengths; mathematical model; molecular dynamics; molecular polarity; protein denaturation; protein folding; protein sequence; protein structure; thermodynamics

We aim to develop first-principles theory for protein stability. The successes of first generation theory indicate that the prediction of protein stability from the amino acid sequence is now within reach. This is a necessary and important step on the much longer road to predicting protein structures from amino acid sequences. A framework which can incorporate and unify for the first time free energy contributions due to helix-coil, hydrophobic, electrostatic, and elastic and excluded volume entropic forces is proposed. The following problems will be attacked: (i) Zimm-Bragg-type theory accounts for polypeptide behaviors driven by "local" interactions among neighbors in the chain sequence. Polymer collapse and folding is driven by "nonlocal" interactions. To understand the full range of protein behaviors, we will incorporate both types of interaction into a single framework. (ii) The mean-field theory will be broadened to treat aspects of intermediate states and folding kinetics, (iii) Electrostatics will be (a) refined to improve predictions of the radius of highly charged unfolded states, (b) refined to account for discrete charge effects, and (c) applied to predicting protein aggregation. (iv) Side chain degrees of freedom will be incorporated into the entropy of folding. (v) The temperature dependence of polar group interactions will be taken into account, and effects of disulfides and other constraints on protein stability will be treated. Our aim is to produce theory and computer software that will predict the largeconformational-change properties of proteins. It will take as input the amino acid sequence, and produce as output phase diagrams which predict radii, solvent exposures, stabilities, charge state, aggregation state, and state transitions as functions of solution conditions.

我们的目标是发展蛋白质稳定性的第一原理理论。 的 第一代理论的成功表明， 氨基酸序列的蛋白质稳定性现在触手可及。 这是在更长的道路上迈出的必要和重要的一步， 从氨基酸序列预测蛋白质结构。 一个框架 它可以第一次整合和统一自由能 由于螺旋线圈，疏水，静电和弹性的贡献 提出了排斥体积熵力的概念。 以下问题 将被攻击： (i)Zimm-Bragg型理论解释了多肽的行为， 在链序列中的邻居之间的“局部”相互作用。 聚合物 塌缩和折叠是由“非局部”相互作用驱动的。 到 了解蛋白质行为的全部范围，我们将结合两者 将不同类型的交互整合到一个框架中。 (ii)平均场理论将被扩展到处理 中间状态和折叠动力学， (iii)静电学将（a）改进，以提高预测的 高度带电的未折叠状态的半径，（B）被细化以解释 离散电荷效应，和（c）应用于预测蛋白质 聚合来 (iv)侧链的自由度将并入熵 折叠。 (v)将采取极性基团相互作用的温度依赖性 以及二硫化物和其他限制对蛋白质的影响 稳定性将得到处理。 我们的目标是产生理论和计算机软件， 蛋白质的大构象变化特性。 这将需要作为 输入氨基酸序列，并生成输出相图 其预测半径、溶剂暴露、稳定性、电荷状态， 聚合状态和作为解的函数的状态转换 条件