Flexible Topology: A Dynamic Model of a Continuous Chemical Space
Flexible Topology: A Dynamic Model of a Continuous Chemical Space
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DOI：
10.1021/acs.jctc.3c00409
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发表时间：
2023-07-24
影响因子：
5.5
通讯作者：
Dickson，Alex
中科院分区：
文献类型：
--
作者：
Donyapour，Nazanin;Fathi Niazi，Fatemeh;Dickson，Alex
配体设计问题涉及为具有一组所需性质的分子搜索化学空间。由于化学空间是离散的，这种搜索必须以逐点的方式进行，每次单独研究一个分子，这可能是低效的。我们提出了一种称为“灵活拓扑”的方法，其中配体由一组变形的“幽灵”原子组成，其原子身份和连接性可以在模拟过程中动态变化。鬼原子被引导到他们的目标位置使用的平移，旋转和索引不变的约束势。这是迈向化学空间连续模型的第一步，其中动态模拟可以通过遵循势能函数的梯度从一个分子移动到另一个分子。这建立在分子动力学模拟领域炼金术的实质性历史上，包括由布鲁克斯及其同事开发的λ动力学方法[X. Kong和C.L.布鲁克斯III，J.Chem.Phys.105，2414（1996）]，但是通过将一组四个动力学属性与每个变形幽灵原子相关联而将其发挥到极致，所述变形幽灵原子不仅控制其存在，而且控制其原子身份。在这里，我们概述了这种方法的理论细节，它的实施使用OpenMM模拟包，和一些初步研究的幽灵粒子组装模拟在真空中。我们研究了一组10个小分子，大小从6到50个原子不等，并表明灵活的拓扑结构能够始终如一地组装所有这些分子到高精度，从随机初始化的位置和属性开始。
Ligand design problems involve searching chemical space for a molecule with a set of desired properties. As chemical space is discrete, this search must be conducted in a pointwise manner, separately investigating one molecule at a time, which can be inefficient. We propose a method called “Flexible Topology”, where a ligand is composed of a set of shapeshifting “ghost” atoms, whose atomic identities and connectivity can dynamically change over the course of a simulation. Ghost atoms are guided toward their target positions using a translation-, rotation-, and index-invariant restraint potential. This is the first step toward a continuous model of chemical space, where a dynamic simulation can move from one molecule to another by following gradients of a potential energy function. This builds on a substantial history of alchemy in the field of molecular dynamics simulation, including the Lambda dynamics method developed by Brooks and co-workers [X. Kong and C.L. Brooks III, J. Chem. Phys. 105, 2414 (1996)], but takes it to an extreme by associating a set of four dynamical attributes with each shapeshifting ghost atom that control not only its presence but also its atomic identity. Here, we outline the theoretical details of this method, its implementation using the OpenMM simulation package, and some preliminary studies of ghost particle assembly simulations in vacuum. We examine a set of 10 small molecules, ranging in size from 6 to 50 atoms, and show that Flexible Topology is able to consistently assemble all of these molecules to high accuracy, beginning from randomly initialized positions and attributes.