Misfolded Cu/Zn superoxide dismutase enzyme (SOD1) shows prion-like propagation in neuronal cells leading to neurotoxic aggregates that are implicated in amyotrophic lateral sclerosis (ALS). Tryptophan-32 (W32) in SOD1 is part of a potential site for templated conversion of wild type SOD1. This W32 binding site is located on a convex, solvent exposed surface of the SOD1 suggesting that hydration effects can play an important role in ligand recognition and binding. A recent X-ray crystal structure has revealed that 5-Fluorouridine (5-FUrd) binds at the W32 binding site and can act as a pharmacophore scaffold for the development of anti-ALS drugs. In this study, a new protocol is developed to account for structural (non-displaceable) water molecules in docking simulations and successfully applied to predict the correct docked conformation binding modes of 5-FUrd at the W32 binding site. The docked configuration is within 0.58 Å (RMSD) of the observed configuration. The docking protocol involved calculating a hydration structure around SOD1 using molecular theory of solvation (3D-RISM-KH, 3D-Reference Interaction Site Model-Kovalenko-Hirata) whereby, non-displaceable water molecules are identified for docking simulations. This protocol was also used to analyze the hydrated structure of the W32 binding site and to explain the role of solvation in ligand recognition and binding to SOD1. Structural water molecules mediate hydrogen bonds between 5-FUrd and the receptor, and create an environment favoring optimal placement of 5-FUrd in the W32 binding site.

中文翻译：

---

水合效应在5-氟尿苷与SOD1结合中的作用：基于新的基于3D-RISM-KH的方案的见解，该方案将结构水包括在对接模拟中。

错折叠的Cu / Zn超氧化物歧化酶（SOD1）在神经元细胞中显示病毒样繁殖，导致神经毒性聚集体，与肌萎缩性侧索硬化症（ALS）有关。SOD1中的色氨酸32（W32）是野生型SOD1模板化转化的潜在位点的一部分。该W32结合位点位于SOD1的凸面，暴露于溶剂的表面，这表明水合作用可以在配体识别和结合中发挥重要作用。最近的X射线晶体结构表明，5-氟尿苷（5-FUrd）在W32结合位点结合，并且可以用作开发抗ALS药物的药效团支架。在这项研究中，开发了一种新协议以在对接模拟中解决结构（不可移位）水分子的问题，并成功地应用于预测W32结合位点上5-FUrd的正确对接构象结合模式。对接配置在观察配置的0.58Å（RMSD）范围内。对接方案涉及使用溶剂化分子理论（3D-RISM-KH，3D-参考相互作用部位模型-Kovalenko-平田）计算SOD1周围的水合结构，从而确定不可置换的水分子用于对接模拟。该协议还用于分析W32结合位点的水合结构，并解释溶剂化在配体识别和与SOD1结合中的作用。结构性水分子介导5-FUrd与受体之间的氢键，