On the estimation of the molecular inaccessible volume and the molecular accessible surface of a ligand in protein–ligand systems,Molecular Systems Design & Engineering

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On the estimation of the molecular inaccessible volume and the molecular accessible surface of a ligand in protein–ligand systems
Molecular Systems Design & Engineering ( IF 3.2 ) Pub Date : 2021-08-12 , DOI: 10.1039/d1me00053e
Konstantinos Konstantinidis ₁ , Ioannis Karakasiliotis ₁ , Kostas Anagnostopoulos ₂ , Georgios C. Boulougouris ₃

Affiliation

In this paper, a novel approach is proposed based on the accurate computation of the inaccessible volume and the corresponding surface area which is defined by the locus of points where a ligand molecule can be placed so that it “touches” a protein molecule at a preset minimum interatomic distance without resulting in overlaps between the atoms of the protein and the atoms of the ligand. The proposed approach can be considered an extension of the widely used concept of the solvent accessible surface area (SASA). The SASA is defined as the surface where a solvent molecule can be in contact with the initial one without any overlaps. This excluded volume interaction is evaluated by treating atoms as hard core spheres, with the limitation of the solvent molecule being represented as a single sphere. In the proposed concepts of the molecular accessible surface (MASA) and the molecular inaccessible volume (MIV) we have practically removed this limitation and all atoms, both in the initial and the “inserted” molecules, are represented as hard spheres. In this paper we focus our examples on biological systems, especially on studying protein–ligand systems, since we expect that this will be one of the most promising fields of applications where the MASA and MIV extensions of the SASA will be of practical and immediate use. Therefore, the MASA and MIV are evaluated based on the surface generated by the ligand while it is being rolled over on all the atoms of the protein without penetrating them. Identification of the inaccessible volume of each candidate protein–ligand pair is also provided in the context of this study, along with the boundary surface where the ligand can be placed so as to be in “contact” with the protein. The proposed concepts of the MASA and MIV are expected to significantly enhance the ability to investigate specific protein–drug interactions by explicitly taking into account the polyatomic nature of a ligand. Several trials have been conducted using the analytical method of Dodd and Theodorou leading to accurate volume and surface area measurements of an arbitrary set of fused spheres in systems of various scales.

中文翻译：

关于蛋白质-配体系统中配体的分子不可及体积和分子可及表面的估计

在本文中，提出了一种新方法，该方法基于不可接近体积和相应表面积的准确计算，该表面积由可以放置配体分子的点的轨迹定义，以便它以预设的方式“接触”蛋白质分子不会导致蛋白质原子和配体原子之间重叠的最小原子间距离。所提出的方法可以被认为是广泛使用的溶剂可及表面积 (SASA) 概念的扩展。SASA 被定义为溶剂分子可以与初始分子接触而没有任何重叠的表面。这种排除的体积相互作用是通过将原子视为硬核球体来评估的，溶剂分子的限制被表示为单个球体。在分子可及表面 (MASA) 和分子不可及体积 (MIV) 的提议概念中，我们实际上已经消除了这一限制，并且初始分子和“插入”分子中的所有原子都表示为硬球。在本文中，我们将示例重点放在生物系统上，特别是研究蛋白质-配体系统，因为我们预计这将是最有前途的应用领域之一，其中 SASA 的 MASA 和 MIV 扩展将具有实际和直接的用途. 因此，MASA 和 MIV 是根据配体在蛋白质的所有原子上滚动而不穿透它们时产生的表面来评估的。本研究还提供了每个候选蛋白质-配体对难以接近的体积的鉴定，连同可以放置配体以便与蛋白质“接触”的边界表面。通过明确考虑配体的多原子性质，预计 MASA 和 MIV 的拟议概念将显着提高研究特定蛋白质-药物相互作用的能力。已经使用 Dodd 和 Theodorou 的分析方法进行了多项试验，从而对各种尺度系统中的任意一组熔融球体进行准确的体积和表面积测量。

更新日期：2021-09-02

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