Open Force Field BespokeFit: Automating Bespoke Torsion Parametrization at Scale.
Open Force Field BespokeFit: Automating Bespoke Torsion Parametrization at Scale.
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DOI：
10.1021/acs.jcim.2c01153
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发表时间：
2022-11-28
影响因子：
5.6
通讯作者：
Cole, Daniel J.
中科院分区：
文献类型：
--
作者：
Horton, Joshua T.;Boothroyd, Simon;Wagner, Jeffrey;Mitchell, Joshua A.;Gokey, Trevor;Dotson, David L.;Behara, Pavan Kumar;Ramaswamy, Venkata Krishnan;Mackey, Mark;Chodera, John D.;Anwar, Jamshed;Mobley, David L.;Cole, Daniel J.
精确的可转移力场的发展是实现原子模型在生物过程研究中的全部潜力的关键，例如用于药物发现的蛋白质-配体结合。最先进的可转移力场，如开放力场计划所产生的力场，使用现代软件工程和自动化技术来提高精度。然而，力场扭转参数，这必须考虑到许多立体电子和立体效应，被认为是比其他力场参数转移少，因此往往是定制参数化的目标。在这里，我们提出了开放力场QCSubmit和BespokeFit软件包，当结合起来，便于扭转参数的拟合量子力学参考数据的规模。我们演示了使用QCSubmit来简化创建和存档大量量子化学计算的过程，通过生成671个药物样片段扭转扫描的数据集。我们使用BespokeFit来推导这些分子中每个分子的各个扭转参数，从而将势能面的均方根误差从使用原始可转移力场的1.1 kcal/mol降低到使用定制版本的0.4 kcal/mol。此外，我们采用定制的力场来计算TYK 2蛋白的同类系列抑制剂的相对结合自由能，并证明准确性的进一步提高，与基础力场相比（MUE从0.560.390.77降低到0.420.280.59 kcal/mol，R2相关性从0.720.350.87提高到0.930.840.97）。
The development of accurate transferable force fields is key to realizing the full potential of atomistic modeling in the study of biological processes such as protein–ligand binding for drug discovery. State-of-the-art transferable force fields, such as those produced by the Open Force Field Initiative, use modern software engineering and automation techniques to yield accuracy improvements. However, force field torsion parameters, which must account for many stereoelectronic and steric effects, are considered to be less transferable than other force field parameters and are therefore often targets for bespoke parametrization. Here, we present the Open Force Field QCSubmit and BespokeFit software packages that, when combined, facilitate the fitting of torsion parameters to quantum mechanical reference data at scale. We demonstrate the use of QCSubmit for simplifying the process of creating and archiving large numbers of quantum chemical calculations, by generating a dataset of 671 torsion scans for druglike fragments. We use BespokeFit to derive individual torsion parameters for each of these molecules, thereby reducing the root-mean-square error in the potential energy surface from 1.1 kcal/mol, using the original transferable force field, to 0.4 kcal/mol using the bespoke version. Furthermore, we employ the bespoke force fields to compute the relative binding free energies of a congeneric series of inhibitors of the TYK2 protein, and demonstrate further improvements in accuracy, compared to the base force field (MUE reduced from 0.560.390.77 to 0.420.280.59 kcal/mol and R2 correlation improved from 0.720.350.87 to 0.930.840.97).
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DOI：
10.1021/acs.jpca.0c10845
发表时间：
2021-04-01
期刊：
The journal of physical chemistry. A
影响因子：
--
作者：
Kania A;Sarapata K;Gucwa M;Wójcik-Augustyn A
通讯作者：
Wójcik-Augustyn A
影响因子：
8.6
作者：
Heller SR;McNaught A;Pletnev I;Stein S;Tchekhovskoi D
通讯作者：
Tchekhovskoi D
影响因子：
1.1
作者：
GODBOUT, N;SALAHUB, DR;WIMMER, E
通讯作者：
WIMMER, E
影响因子：
4.4
作者：
BECKE, AD
通讯作者：
BECKE, AD
影响因子：
8.4
作者：
Gapsys V;Pérez-Benito L;Aldeghi M;Seeliger D;van Vlijmen H;Tresadern G;de Groot BL
通讯作者：
de Groot BL