Fast Computations for Structural Transitions in Proteins

蛋白质结构转变的快速计算

• 批准号: 6865672
• 负责人: DANIEL M ZUCKERMAN
• 金额: $ 21.79万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865672
• 关键词: bioengineering /biomedical engineering; calmodulin; computer program /software; computer simulation; computer system design /evaluation; conformation; molecular dynamics; myosins; protein structure; structural biology

DESCRIPTION (provided by applicant): The lack of reliable descriptions of conformational transitions in proteins represents a critical gap in the body of structural biology knowledge. Not only are conformational transitions at the heart of many proteins' functions --- from enzymes to motor proteins --- but structural intermediates also serve as a well-established class of targets for transition-state inhibitor drugs. We therefore propose a novel computational approach to study the dramatic conformational transitions in (a) calmodulin (CAM), which mediates essential processes from gene expression to muscle contraction to mitosis, and (b) myosin, the protein motor that causes muscle contraction. The new protocol will build on extremely promising preliminary results, which demonstrate unprecedented access to physiological timescales. Combining residue-level modeling and fine-grid discretization, the approach has already proven capable of unbiased dynamic simulation of dozens of conformational transitions in each of the two 72-residue domains of calmodulin. In fact, the protocol generates several transition events per day on an inexpensive, single-processor desktop computer. This high efficiency will enable the study of myosin with modest computer resources. A multi-level approach to modeling is central to this proposal. Results generated from initial "coarse grained" models (e.g., residue-level) will be refined using a series of progressively more accurate force fields. Combined with the high-quality sampling enabled by discretization, multi-level modeling will permit a high degree of confidence in the computational data. Indeed, the simulation results --- including models of structural intermediates and the identities of kinetically critical residues --- will be used to design experiments (to be performed by collaborators) aimed toward improving our detailed understanding of structural events. Because of its speed and simplicity, the new protocol forms an ideal basis for a software tool of value to expert and non-expert alike. A detailed plan for distributing user-friendly software packages is presented, and the source code will be available for modification by expert users.

描述（由申请人提供）：缺乏蛋白质中构象转变的可靠描述代表了结构生物学知识体内的关键差距。从酶到运动蛋白的许多蛋白质功能的核心构象转变不仅是构象转变---而且结构中间体也是过渡态抑制剂药物的一类靶标。因此，我们提出了一种新型的计算方法，以研究（a）钙调蛋白（CAM）中的急剧构象转变，该方法介导了从基因表达到肌肉收缩到有丝分裂的基本过程，以及（b）肌球蛋白，这是导致肌肉收缩的蛋白质运动。新协议将基于极其有希望的初步结果，这表明可以访问生理时间标准。该方法结合了残基级建模和细网格离散化，已经证明能够在两个72个钙调蛋白的两个72个残留域中的数十个构象转变进行无偏的动态模拟。实际上，该协议每天在廉价的单处理器台式计算机上每天生成多个过渡事件。这种高效率将通过适度的计算机资源来研究肌球蛋白。建模的多层次方法是该建议的核心。最初的“粗粒”模型（例如，残基级）产生的结果将使用一系列逐渐更准确的力场进行完善。结合由离散化启用的高质量抽样，多级建模将允许对计算数据具有高度的信心。实际上，模拟结果 - 包括结构中间体的模型和动力学关键残基的身份 - 将用于设计实验（由合作者执行），旨在提高我们对结构事件的详细了解。由于其速度和简单性，新协议构成了对专家和非专家的价值工具的理想基础。提出了用于分发用户友好型软件包的详细计划，并且源代码将用于专家用户的修改。