CONFORMATIONAL COUPLING WITH PH IN POLYPEPTIDES

多肽中与 PH 的构象偶联

基本信息

批准号：
6540747
负责人：
HAROLD A. SCHERAGA
金额：
$ 3.36万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-04-01 至 2004-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6540747
关键词：
South America acidity /alkalinity alanine chemical models chemical stability computer simulation computer system design /evaluation conformation copolymer mathematical model model design /development molecular polarity peptides physical state protein folding solutions

项目摘要

The purpose of this proposal is to gain an understanding of the physical reasons for the unusual stabilization of the alpha-helical conformation observed in short alanine-based copolymers. Despite several experimental studies designed to ascertain the relative helix stability of the naturally occurring amino acids in water, using short alanine-based copolymers that incorporate charged and other highly soluble residues to render them soluble, discrepancies still exist regarding the intrinsic helix propensities of some residues, among which, L-alanine is the most notable. There are two disparate views about these discrepancies. The first view relies on both (a) earlier experimental studies in which the amino acids were incorporated as a central block in a tri-block copolymer, or as guests in a water-soluble host polypeptide, with the resulting propensities inferred from the temperature dependence of the helix content; and (b) on recent experimental studies of alanine-rich sequences N-terminally linked to a synthetic helix-inducing template. Their conclusions, supported by additional theoretical evidence, is that alanine is helix indifferent with a Zimm-Bragg propagation parameter near unity. The second view, relying on studies of short sequence-specific peptides involving an alanine host solubilized by a few charged or polar residues within the alanine block, is that alanine is a strong helix-former with a propagation parameter-near two. Resolution of the discrepancies involving the intrinsic helix-forming tendency of alanine is central to the protein folding problem. To provide a computational resolution of this problem, we have recently considered the coupling between conformation and pH to determine the most probable conformation of a polypeptide in solution. Our new approach combines a robust conformational search method with a fast and stable algorithm to solve the Poisson-Boltzmann equation. Recent applications of this methodology to study a series of short oligopeptides have been very successful, and further development and applications of this technique to the present project is foreseen. Additional experiments to test the computational results will be carried out. The proposed studies attempt to resolve the discrepancies between both disparate views, and provide additional insights into the underlying factors that promote the right-handed alpha-helical conformation in water.

该提案的目的是了解在基于丙氨酸的简短共聚物中观察到的α-螺旋构象的异常稳定的物理原因。尽管有一些实验研究旨在确定水中天然氨基酸的相对螺旋稳定性，但使用基于丙氨酸的简短共聚物，这些共聚物结合了充电和其他高度溶解的残基来使其可溶，但在某些残基的固有螺旋倾向上仍然存在差异，其中L-丙氨酸是最明显的。关于这些差异有两种不同的看法。第一个观点依赖于（a）早期的实验研究，在这些研究中，氨基酸被作为三块共聚物中的中心块或水溶性宿主多肽的客人纳入中央块，并根据螺旋含量的温度依赖性推断出的阳性增强性；（b）在最新的富含丙氨酸序列的实验研究中，与合成螺旋诱导模板相关联的N末端。他们的结论得到了其他理论证据的支持，是丙氨酸与统一附近的zimm-bragg传播参数无关。第二种观点依赖于短序列特异性肽的研究，这些肽涉及丙氨酸块中的几个带电或极性残基溶解的丙氨酸宿主，是丙氨酸是具有繁殖螺旋形式的，具有传播参数 - near二。涉及丙氨酸内在螺旋形成趋势的差异的分辨率对于蛋白质折叠问题至关重要。为了提供该问题的计算分辨率，我们最近考虑了构象与pH之间的耦合，以确定溶液中多肽最可能的构象。我们的新方法将强大的构象搜索方法与快速，稳定的算法结合在一起，以求解泊松 - 波尔茨曼方程。该方法在研究一系列短寡肽方面的最新应用非常成功，并且预计该技术在本项目中的进一步开发和应用。测试计算结果的其他实验将进行。拟议的研究试图解决两种不同观点之间的差异，并提供对促进水中右手α螺旋构象的潜在因素的更多见解。