Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States.
J Phys Chem B. 2022 Sep 8;126(35):6642-6653. doi: 10.1021/acs.jpcb.2c04245. Epub 2022 Aug 25.
Molecular dynamic simulations are an effective tool to study complex molecular systems and are contingent upon the availability of an accurate and reliable molecular mechanics force field. The Drude polarizable force field, which allows for the explicit treatment of electronic polarization in a computationally efficient fashion, has been shown to reproduce experimental properties that were difficult or impossible to reproduce with the CHARMM additive force field, including peptide folding cooperativity, RNA hairpin structures, and DNA base flipping. Glycoproteins are essential components of glycoconjugate vaccines, antibodies, and many pharmaceutically important molecules, and an accurate polarizable force field that includes compatibility between the protein and carbohydrate aspect of the force field is essential to study these types of systems. In this work, we present an extension of the Drude polarizable force field to glycoproteins, including both N- and O-linked species. Parameter optimization focused on the dihedral terms using a reweighting protocol targeting NMR solution -coupling data for model glycopeptides. Validation of the model include eight model glycopeptides and four glycoproteins with multiple N- and O-linked glycosylations. The new glycoprotein carbohydrate force field can be used in conjunction with the remainder of Drude polarizable force field through a variety of MD simulation programs including GROMACS, OPENMM, NAMD, and CHARMM and may be accessed through the Drude Prepper module in the CHARMM-GUI.
分子动力学模拟是研究复杂分子系统的有效工具，而这依赖于准确可靠的分子力学力场。可以明确处理电子极化的 Drude 极化力场，已经被证明可以重现实验性质，而这些性质用 CHARMM 添加力场很难或不可能重现，包括肽折叠协同性、RNA 发夹结构和 DNA 碱基翻转。糖蛋白是糖缀合物疫苗、抗体和许多重要药物分子的重要组成部分，因此需要一个准确的极化力场，该力场包含蛋白质和糖基部分之间的兼容性，以便研究这些类型的系统。在这项工作中，我们提出了一种 Drude 极化力场的扩展，包括 N-和 O-连接的糖蛋白。参数优化主要针对二面角项，使用重新加权协议针对 NMR 溶液耦合数据进行模型糖肽的目标。模型的验证包括 8 个模型糖肽和 4 个具有多个 N-和 O-连接糖基化的糖蛋白。新的糖蛋白碳水化合物力场可以与 Drude 极化力场的其余部分一起使用，通过各种 MD 模拟程序，包括 GROMACS、OPENMM、NAMD 和 CHARMM，并且可以通过 CHARMM-GUI 中的 Drude Prepper 模块访问。
