Department of Life Sciences, University of Roehampton, London SW15 4JD, UK.
Department of Physiology and Biophysics, Weill Cornell Medical College of Cornell University (WCMC), New York, NY 10065, USA.
Methods. 2021 Jan;185:3-14. doi: 10.1016/j.ymeth.2020.02.009. Epub 2020 Feb 17.
Molecular dynamics (MD) simulations have developed into an invaluable tool in bimolecular research, due to the capability of the method in capturing molecular events and structural transitions that describe the function as well as the physiochemical properties of biomolecular systems. Due to the progressive development of more efficient algorithms, expansion of the available computational resources, as well as the emergence of more advanced methodologies, the scope of computational studies has increased vastly over time. We now have access to a multitude of online databases, software packages, larger molecular systems and novel ligands due to the phenomenon of emerging novel psychoactive substances (NPS). With so many advances in the field, it is understandable that novices will no doubt find it challenging setting up a protein-ligand system even before they run their first MD simulation. These initial steps, such as homology modelling, ligand docking, parameterization, protein preparation and membrane setup have become a fundamental part of the drug discovery pipeline, and many areas of biomolecular sciences benefit from the applications provided by these technologies. However, there still remains no standard on their usage. Therefore, our aim within this review is to provide a clear overview of a variety of concepts and methodologies to consider, providing a workflow for a case study of a membrane transport protein, the full-length human dopamine transporter (hDAT) in complex with different stimulants, where MD simulations have recently been applied successfully.
分子动力学 (MD) 模拟已经成为双分子研究中非常有价值的工具，因为该方法能够捕捉描述生物分子系统功能以及物理化学性质的分子事件和结构转变。由于更高效的算法不断发展，可用计算资源不断扩大，以及更先进的方法学的出现，计算研究的范围随着时间的推移而大大增加。由于新兴精神活性物质 (NPS) 的出现，我们现在可以访问大量的在线数据库、软件包、更大的分子系统和新型配体。由于该领域的众多进展，新手在运行第一次 MD 模拟之前无疑会发现设置蛋白-配体系统具有挑战性，这是可以理解的。这些初始步骤，如同源建模、配体对接、参数化、蛋白准备和膜设置，已成为药物发现管道的基本组成部分，许多生物分子科学领域都受益于这些技术的应用。然而，它们的使用仍然没有标准。因此，我们在这篇综述中的目标是提供对各种概念和方法学的清晰概述，为案例研究提供工作流程，该案例研究是一种膜转运蛋白，全长人类多巴胺转运蛋白 (hDAT) 与不同兴奋剂复合物，最近成功应用了 MD 模拟。
