Biomolecular Simulations of Halogen Bonds with a GROMOS Force Field,Journal of Chemical Theory and Computation

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Biomolecular Simulations of Halogen Bonds with a GROMOS Force Field
Journal of Chemical Theory and Computation ( IF 5.7 ) Pub Date : 2018-09-14 00:00:00 , DOI: 10.1021/acs.jctc.8b00278
Rafael Nunes _{1,

2,

3} , Diogo Vila-Viçosa _{1,

2} , Miguel Machuqueiro _{1,

2} , Paulo J. Costa _{1,

2}

Affiliation

Halogen bonds (XBs) are non-covalent interactions in which halogens (X), acting as electrophiles, interact with Lewis bases. XBs are able to mediate protein–ligand recognition and therefore play an important role in rational drug design. In this context, the development of molecular modeling tools that can tackle XBs is paramount. XBs are predominantly explained by the existence of a positive region on the electrostatic potential of X named the σ-hole. Typically, with molecular mechanics force fields, this region is modeled using a charged extra point (EP) linked to X along the R–X covalent bond axis. In this work, we developed the first EP-based strategy for GROMOS force fields (specifically GROMOS 54A7) using bacteriophage T4 lysozyme in complex with both iodobenzene and iodopentafluorobenzene as a prototype system. Several EP parametrization schemes were tested by adding a virtual interaction site to ligand topologies retrieved from the Automated Topology Builder (ATB) and Repository. Contrary to previous approaches using other force fields, our analysis is based on the capability of each parametrization scheme to sample XBs during MD simulations. Our results indicate that the implementation of an EP at a distance from iodine corresponding to R_min provides a good qualitative description of XBs in MD simulations, supporting the compatibility of our approach with the GROMOS 54A7 force field.

中文翻译：

具有GROMOS力场的卤素键的生物分子模拟

卤素键（XBs）是非共价相互作用，其中作为亲电子试剂的卤素（X）与Lewis碱相互作用。XB能够介导蛋白质-配体识别，因此在合理的药物设计中起着重要的作用。在这种情况下，开发能够解决XB的分子建模工具至关重要。XB的主要原因是X的静电势上存在一个称为σ孔的正区域。通常，在分子力学力场的情况下，该区域使用沿R–X共价键轴与X相连的带电加点（EP）进行建模。在这项工作中，我们开发了第一个基于EP的GROMOS力场（特别是GROMOS 54A7）的策略，使用了噬菌体T4溶菌酶与碘苯和碘五氟苯一起作为原型系统。通过向从自动拓扑生成器（ATB）和存储库中检索到的配体拓扑中添加虚拟交互位点，对几种EP参数化方案进行了测试。与先前使用其他力场的方法相反，我们的分析基于每种参数化方案在MD模拟过程中对XB进行采样的能力。我们的结果表明，在距碘一定距离的地方实施EP对应于R _min为MD模拟中的XB提供了很好的定性描述，支持了我们的方法与GROMOS 54A7力场的兼容性。

更新日期：2018-09-14

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