PROTEIN STRUCTURE VIA QUANTUM CHEMISTRY AND NMR

通过量子化学和核磁共振研究蛋白质结构

• 批准号: 2188684
• 负责人: Eric Oldfield
• 金额: $ 18.14万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2188684
• 关键词: calmodulin; carbon; chemical bond; chemical models; computer program /software; computer simulation; interleukin 1; interleukin 8; mathematical model; method development; molecular dynamics; molecular orbital; nitrogen; nuclear magnetic resonance spectroscopy; nuclease; protein folding; protein structure; quantum chemistry; stable isotope; structural biology; supercomputer; ubiquitin

The broad, long term objective of this research is to develop new ways of predicting, refining and validating protein structures, both in solution, in membranes, and in the crystalline solid state. The health relatedness is that detailed knowledge of protein structure should lead to new ways of investigating function, such as peptide - calmodulin interactions, interleukin-receptor interactions, and protein-inhibitor interactions. In this work, we will develop use of the nuclear magnetic resonance (NMR) chemical shift of primarily 13C and 15N nuclei in proteins as novel probes of structure. In particular, we will compute the Ramachandran shielding surfaces for many heavy atoms in the naturally occurring amino-acids, then use these shielding surfaces to predict and refine structure using a Z- surface approach, and back calculation. The use of chemical shifts as structural restraints has recently been made possible by using quantum chemical methods on high performance workstations. The shielding surfaces we develop will be made available to other groups, and will enable incorporation of many hundreds - perhaps up to approx. 1000 heavy atom chemical shift restraints into protein structure determinations. The effects of molecular motion on observed chemical shifts will be investigated by using molecular dynamics shielding trajectories, combined with shielding surfaces and bond length and bond angle shielding derivatives. Information on which force fields in energy minimization/molecular dynamics best describe protein structure will be obtained from the work proposed. Initial proteins to be investigated include the cytokines interleukin-1beta and interleukin-8, ubiquitin, as well as calmodulin and calmodulin-peptide complexes. Suitable data files for refinement will be obtained from A. Gronenborn, G.M. Clore and J. Wand. This work will provide a unique approach to the refinement and determination of protein structure, will be applicable to both solution, membrane and crystalline solid-state structure analysis, and should thus be of great interest to many groups working on protein structure refinement/determination using x-ray diffraction, nuclear magnetic resonance spectroscopy, as well as computational chemistry.

这项研究的广泛、长期的目标是开发新的方法 预测、提纯和验证蛋白质结构，无论是在溶液中， 在膜中，以及在结晶固态中。与健康相关的 对蛋白质结构的详细了解应该会带来新的方法 研究功能，如多肽-钙调蛋白相互作用， 白细胞介素受体的相互作用和蛋白质抑制物的相互作用。在……里面 在这项工作中，我们将开发利用核磁共振(核磁共振) 蛋白质中主要13C和15N核的化学位移作为新的探针 在结构上。特别是，我们将计算拉马钱德兰屏蔽 自然产生的氨基酸中许多重原子的表面，然后 使用这些屏蔽面来预测和改进结构，使用Z- 曲面逼近和反演算。使用化学位移作为 最近，通过使用量子技术，结构约束成为可能 高性能工作站上的化学方法。屏蔽面 我们的开发将提供给其他团体，并将使 成百上千的公司--可能高达大约。1000个重原子 蛋白质结构测定中的化学位移限制。这个 分子运动对观察到的化学位移的影响将是 使用分子动力学屏蔽轨迹进行研究，结合 具有屏蔽面和粘接长度和粘合角度屏蔽 衍生品。关于能量中哪些力场的信息 最小化/分子动力学最好地描述了蛋白质结构 从建议的工作中获得。待研究的初始蛋白质 包括细胞因子IL-1β和IL-8，泛素，AS 以及钙调蛋白和钙调蛋白-多肽复合体。合适的数据文件 将从A.GronenBorn、G.M.Clore和J.Wand那里获得改进。 这项工作将提供一种独特的方法来细化和 蛋白质结构的测定，将适用于两种溶液， 膜和晶体的固态结构分析，因此应该 引起了许多致力于蛋白质结构研究的小组的极大兴趣 利用核磁X射线衍射法进行精制/测定 共振光谱学，以及计算化学。