Combining molecular dynamics simulations with crystallographic refinement

将分子动力学模拟与晶体学细化相结合

• 批准号: 9243621
• 负责人: David A Case
• 金额: $ 26.69万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243621
• 关键词: Adoption; Algorithms; Amber; Area; Attention; Behavior; Biomedical Research; Cells; Complement; Complex; Computer software; Coupled; Crystallization; Data; Development; Disease; Drug Design; Environment; Feedback; Generations; Goals; Heterogeneity; Hour; Integral Equation; Ions; Lead; Methods; Modeling; Modernization; Molecular; Molecular Conformation; Motion; Nucleic Acids; Periodicity; Preparation; Procedures; Process; Proteins; Protocols documentation; Resolution; Roentgen Rays; Running; Sampling; Solvents; Structure; Technology; Testing; Time; Water; Work; X-Ray Crystallography; base; cofactor; crystallinity; density; drug discovery; electron density; improved; insight; method development; molecular dynamics; molecular mechanics; novel; restraint; simulation; statistics; structural biology; tool

The principal goals of this project are the development of algorithms that allow one to make better con- nections between molecular simulations using force fields and the interpretation of crystallographic data on biomolecules. This will involve the following components: Improved models for X-ray scattering from bulk solvent. Most crystallographic refinements protocols try to place a few “ordered” solvent (water) molecules into the observed density, and treat the remaining solvent space as arising from a flat density. Neither part of this model is physcially correct: very few solvent molecules are really ordered, and the bulk is far from flat. This project will explore alternate methods for describing the scattering contribution from solvent, based on integral equation models and explicit molecular dynamics simulations. This is expected to lead to a more correct description of the solvent environment, which it turn should lead to more accurate electron densities and interpretations for the biomolecules themselves Improved models for biomolecular motion and conformational heterogeneity. The standard model for crys- tallographic refinement treats motion and heterogenety via optimization of atomic displacement parame- ters (ADPs) and some combination of rigid-body (TLS) motions for certain subsets of the biomolecule, along with the specification of “alternate conformations” where this can be determined from an examina- tion of the density. The proper description of correlated motions in crystals is likely to be key in obtaining better models for X-ray scattering, but relatively little is known about what motional models are the most physically realistic. Molecular dynamics simulations of super-cells (many unit cells) of biomolecular crys- tals will be used to examine these issues, with particular attention to the question of how well refined TLS parameters are likely to correspond to physical motions. Using modern force fields to guide X-ray refinement. My group has collaborated for about two years with the Phenix development team to create a software environment that can use modern force fields (as imple- mented, for now, in the Amber simulation package) to complement or replace geometric restraints of the Engh-Huber variety with the forces arising from a periodic molecular mechanics model. The initial version of this will be released in the Spring of 2016, and goes a long way towards automating the process from a user's perspective: running a preparation script and setting useAmber=true is often enough to turn on the new procedure. But much remains to be done: allowing for alternate conformations, ensemble-based refinement, and incorporation of implicit solvent models in a periodic environment will be top priorities, as will be more extended testing and incorporation of user feedback.

该项目的主要目标是开发算法，使人们能够更好地控制 使用力场的分子模拟与晶体学数据的解释之间的联系 这将涉及以下组成部分： 大多数晶体学精修方案都尝试改进本体溶剂的 X 射线散射模型。 将一些“有序”溶剂（水）分子放入观察到的密度中，并处理剩余的溶剂 该模型的两个部分在物理上都不正确：溶剂很少。 分子确实是有序的，并且整体远非平坦。该项目将探索替代方法。 用于描述溶剂的散射贡献，基于积分方程模型和显式 分子动力学模拟预计将导致对溶剂的更正确的描述。 环境，这应该会导致更准确的电子密度和对 生物分子本身 改进的生物分子运动和构象异质性模型。 塔图细化通过原子位移参数的优化来处理运动和异质性 生物分子的某些子集（ADP）和刚体（TLS）运动的某种组合， 以及“替代构象”的规范，这可以通过检查来确定 晶体中相关运动的正确描述可能是获得密度的关键。 更好的 X 射线散射模型，但对于哪些运动模型是最重要的模型知之甚少 生物分子晶体的超级细胞（许多单位细胞）的分子动力学模拟。 tals 将用于检查这些问题，特别关注 TLS 的完善程度问题 参数可能对应于物理运动。 使用现代力场来引导 X 射线精化 我的团队已经与该公司合作了大约两年。 Phoenix 开发团队创建了一个可以使用现代力场的软件环境（如实施例） 目前，在 Amber 模拟包中）以补充或取代几何约束 Engh-Huber 与周期性分子力学模型产生的力的变化 初始版本。 其中的内容将于 2016 年春季发布，这对于实现流程自动化大有帮助。 用户的角度：运行准备脚本并设置 useAmber=true 通常足以打开 但还有很多工作要做：允许基于整体的替代构象。 改进以及将隐式溶剂模型纳入周期性环境将是首要任务，因为 将进行更广泛的测试并纳入用户反馈。