Research and deployment of binding-domain flexible MovableType (MTFlex) for free energy-based affinity prediction and crystallographic structure determination

蛋白质/配体结合的研究是计算生物学的核心问题之一，因为其 重要的是了解分子间的相互作用，因为它在药物发现的实际回报， 努力精确的靶标/配体结构在下一代设计中可能产生的变革性影响 药物不能被夸大。如果我们能用这些方法常规而精确地设计分子 它将彻底改变药物发现，通过筛选出没有活性的化合物，同时集中更多的精力， 以及对高活性化合物的详细检查确定小分子（候选药物或先导药物）的结构 与生物受体（与疾病有关的蛋白质）结合的化合物）是该方法中的必要步骤， 药物发现。 在这个建议中，我们描述了一种新的方法，我们称之为MovableType（MT），它解决了蛋白质配体 绑定和评分问题，使用基本的统计力学结合一种新的方式来生成 蛋白质结合口袋中配体的集合。通过快速组装必要的分区函数 我们直接得到结合自由能和低自由能位姿。从概念上讲，MT方法是 类似于块和类型集打印，这使我们能够有效地评估分区函数， 感兴趣的区域或系统。在这种方法中，我们构建了两个数据库，1）描述了 作为r的函数的某些成对相互作用从知识库（蛋白质数据库（PDB）或 剑桥结构数据库（CSD））和2）作为r的函数的成对相互作用的能量学 从经验势中获得，经验势可以从概率中获得，也可以利用现有的成对势。 像琥珀这样的潜力。总之，MT方法是一种通用的方法，可以使用广泛的二体势 功能，并可以扩展到更高阶的相互作用，如果需要。MT方法的最新工作 推出了三个核心产品模块：MTScore（终态和整体结合亲和力预测）， MTDock（配体放置）和MTCS（配体构象搜索）。在这个项目中，我们将扩展我们的MT 产品线，并将此方法交付给X射线晶体学家和计算化学家， 活性位点内和周围的自动化侧链旋转异构体和靶环采样，准确的结合亲和力 预测和最小值选择，以及晶体学密度匹配和放置。这项工作将涉及 开发一种新的集成工具，用于自动化结构/模型制备，旋转异构体/环选择， 旋转异构体/环生成（“MTFlex proper”）、环/总异构体最小化和分析。我们将在商业上部署 我们称之为MTFlex的技术构建了图形用户界面，用于莫伊、Phenix和我们的 基于Web的云平台。最后，将此软件应用于基于真实的生命结构的药物发现问题 与我们的制药合作伙伴（见支持信）。

The study of protein/ligand binding is one of the central problems in computational biology because of its importance in understanding intermolecular interactions, and because of its practical payoff in drug discovery efforts. The transformative impact accurate target/ligand structure can have in the design of next generation medicines cannot be overstated. If we could routinely and accurately design molecules using these approaches it would revolutionize drug discovery by winnowing out compounds with no activity while focusing more effort and scrutiny on highly active compounds. Determining the structure of a small molecule (drug candidate or lead compound) bound to a biological receptor (protein implicated in disease) is a necessary step in this approach to drug discovery. In this proposal we describe a novel method we call MovableType (MT), which addresses the protein ligand binding and scoring problem using fundamental statistical mechanics combined with a novel way to generate the ensemble of a ligand in a protein binding pocket. Via a rapid assembly of the necessary partition functions we directly obtain binding free energies and the low free energy poses. Conceptually, the MT method is analogous to block and type set printing, which allows us to efficiently evaluate partition functions describing regions or systems of interest. In this approach we construct two databases that 1) describe the probability of certain pairwise interactions as a function of r obtained from a knowledge base (Protein Databank (PDB) or the Cambridge Structural Database (CSD)) and 2) the energetics of the pairwise interactions as a function of r obtained from empirical potentials, which can be either derived from the probabilities or can utilize extant pairwise potentials like AMBER. Overall, the MT method is a general one and can use a broad range of two-body potential functions and can be extended to higher-order interactions if so desired. Recent work with the MT method has led to the launch of three core product modules: MTScore (both endstate and ensemble binding affinity prediction), MTDock (ligand placement), and MTCS (ligand conformational search). In this project, we will extend our MT product line and deliver this methodology to X-ray crystallographers and computational chemists for use in automated sidechain rotamer and target loop sampling within and around the active site, accurate binding affinity prediction and minima selection, and crystallographic density matching and placement. This work will involve development of a new, integrated tool for automated structure/model preparation, rotamer/loop selection, rotamer/loop generation (“MTFlex proper”), loop/totamer minimization, and analysis. We will commercially deploy the technology, which we will call MTFlex, construct graphical user interfaces for use in MOE, Phenix, and our web-based cloud platform. Finally, this software will be used in real life structure-based drug discovery problems with our pharmaceutical collaborators (see Letters of Support).