Understanding Essential Protein Dynamics through the Anharmonic Properties of Thermally Excited Vibrations

通过热激发振动的非简谐特性了解基本蛋白质动力学

• 批准号: 10566333
• 负责人: Matthias Heyden
• 金额: $ 22.42万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10566333
• 关键词: Address; Algorithms; Allosteric Site; Binding; Binding Sites; Computer Hardware; Computer software; Computers; Computing Methodologies; Data; Detection; Development; Diffusion; Disease; Drug Binding Site; Drug Design; Drug Targeting; Drug toxicity; Event; Exhibits; Extracellular Matrix Degradation; FDA approved; Face; Family; Freedom; Frequencies; Frustration; Future; Generations; Goals; Homologous Protein; Individual; Inflammatory; Knowledge; Laboratory Research; Lead; Link; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Methodology; Methods; Molecular Conformation; Motion; Neoplasm Metastasis; Pathologic; Pharmaceutical Preparations; Potential Energy; Property; Protein Conformation; Protein Dynamics; Proteins; Protocols documentation; Sampling; Side; Structure; Surface; System; Techniques; Therapeutic Uses; Universities; Validation; chronic inflammatory disease; clinical application; cluster computing; computer framework; computerized tools; conformational conversion; cost; detection method; drug candidate; drug development; drug discovery; drug mechanism; expectation; high dimensionality; inhibitor; interest; interoperability; medication safety; member; millisecond; molecular dynamics; novel; open source; pharmacologic; protein function; rational design; side effect; simulation; small molecule inhibitor; software development; supercomputer; tumor; vibration

The selectivity of orthosteric drugs is often limited by the structural similarity of their binding sites in homologous proteins, while allosteric binding sites are far less conserved. This allows allosteric drugs to bind a target protein with higher selectivity, which reduces the potential for side-effects and lowers drug toxicity. However, allosteric drug discoveries have been limited to serendipitous observations because rational allosteric drug design strategies face several inherent challenges. These challenges are directly related to current limits in the predictability of protein conformational fluctuations and collective dynamics that are central to the mechanisms of allosteric drugs. The objective of this project is the development of computational methods to facilitate the rational design of allosteric drugs via predictions of protein conformational fluctuations and collective dynamics from all-atom simulations. In principle, all-atom molecular dynamics simulations can directly explore protein conformational dynamics but require sampling on timescales of milliseconds to seconds for systems of pharmacological interest. Even with state-of-the-art enhanced sampling techniques, the associated computational costs and hardware requirements (special purpose computers, national supercomputers, large distributed computing networks) limit such applications to a small number of systems. This project aims to make the computational discovery of allosteric mechanisms in proteins more efficient and achievable with computer hardware available in most research laboratories and universities. To this end, the methods developed for this project maximize the information on inherent protein dynamics that can be extracted from molecular dynamics simulations. These methods will initially be applied to identify allosteric mechanisms in matrix metallo-proteinases (MMPs), which represent a family of structurally homologous proteins involved in the degradation of the extracellular matrix. Several members of the MMP family have been identified as drug targets in the context of chronic inflammatory disease and cancer metastasis. MMPs feature a highly conserved catalytic center, which results in a low selectivity of orthosteric small molecule inhibitors for individual MMPs and limits their therapeutic use. This project aims to identify allosteric mechanisms in MMPs that enable the targeted development of highly selective allosteric MMP inhibitors as potential drug candidates. The methods developed for this project are general and not specific to MMPs. They will thus be applicable for the identification of allosteric mechanisms in other drug target proteins and will be made available as open- source software.

邻位构型药物的选择性往往受到它们在同系物中结合部位的结构相似性的限制。 蛋白质，而变构结合部位要保守得多。这使得变构药物可以结合目标蛋白。 具有更高的选择性，从而减少了潜在的副作用，并降低了药物毒性。然而，变构 药物发现一直局限于偶然的观察，因为合理的变构药物设计 战略面临着几个内在的挑战。这些挑战直接与 蛋白质构象波动的可预测性和集体动力学是机制的核心 变构药物。这个项目的目标是开发计算方法，以促进 通过预测蛋白质构象涨落和集体动力学合理设计变构药物 来自全原子模拟。 原则上，全原子分子动力学模拟可以直接探索蛋白质构象动力学，但 对于具有药理意义的系统，要求在毫秒到秒的时间尺度上进行采样。即使是在 最先进的增强采样技术、相关的计算成本和硬件要求 (专用计算机、国家超级计算机、大型分布式计算网络)限制 应用到少数系统。该项目旨在使变构的计算发现 利用大多数研究中可用的计算机硬件更有效和更容易实现蛋白质的机制 实验室和大学。为此，为该项目开发的方法最大限度地提供了关于 可以从分子动力学模拟中提取的固有蛋白质动力学。 这些方法最初将用于鉴定基质金属蛋白酶(MMPs)中的变构机制， 它们代表了参与细胞外降解的一系列结构上同源的蛋白质 矩阵。基质金属蛋白酶家族的几个成员已被确定为慢性前列腺癌的药物靶点 炎症性疾病和癌症转移。MMPs具有高度保守的催化中心，这导致 正构体小分子抑制剂对单个MMPs的选择性较低，限制了其治疗用途。 该项目旨在确定MMPs中的变构机制，使其能够有针对性地开发高度 选择性变构基质金属蛋白酶抑制剂作为潜在的候选药物。 为该项目开发的方法是一般性的，并不是针对MMP的。因此，它们将适用于 鉴定其他药物靶蛋白中的变构机制，并将以开放的形式提供- 源软件。