Combining molecular dynamics simulations with crystallographic refinement

这个项目的主要目标是算法的发展，使人们能够更好地控制。 力场分子模拟与晶体学数据解释之间的联系 在生物分子上。这将涉及以下组成部分： 本体溶剂X射线散射的改进模型。大多数晶体学细化方案试图 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 空间是由一种高密度物质产生的。这个模型的任何一部分都不是物理正确的： 分子是真正有序的，而大部分分子远不是有序的。本项目将探索替代方法 为了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。这有望导致对溶剂的更正确描述 环境，这反过来应该导致更准确的电子密度和解释的 生物分子本身 生物分子运动和构象异质性的改进模型。crys的标准模型- tallographic细化处理运动和不均匀性通过原子位移参数的优化， 和一些刚体（TLS）运动的组合， 沿着“替代构象”的具体说明，其中这可以通过检查确定- 的密度。正确描述晶体中的相关运动可能是获得 更好的X射线散射模型，但相对较少的是知道什么运动模型是最 物理现实。生物分子晶体超胞（多个单胞）的分子动力学模拟 本文将使用这些数据来研究这些问题，并特别关注如何完善TLS的问题 参数可能对应于物理运动。 使用现代力场引导X射线细化。我的团队已经合作了大约两年， 凤凰开发团队创建一个软件环境，可以使用现代力场（简单地说， 目前，在Amber模拟包中已记录），以补充或取代 Engh-Huber变化与周期性分子力学模型产生的力。初始版本 这将在2016年春季发布，并在很长一段时间内实现自动化的过程，从一个 用户视角：运行准备脚本并设置useAmber=true通常足以打开 新的程序。但仍有许多工作要做：允许交替构象， 完善，并在定期环境中纳入隐式溶剂模型将是首要任务， 将进行更广泛的测试并纳入用户反馈。

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.