Huber Roland G, Marzinek Jan K, Holdbrook Daniel A, Bond Peter J
Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Matrix #07-01, 30 Biopolis Street, 138671, Singapore.
Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), Matrix #07-01, 30 Biopolis Street, 138671, Singapore; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore.
Prog Biophys Mol Biol. 2017 Sep;128:121-132. doi: 10.1016/j.pbiomolbio.2016.09.010. Epub 2016 Oct 17.
Viral pathogens are a significant source of human morbidity and mortality, and have a major impact on societies and economies around the world. One of the challenges inherent in targeting these pathogens with drugs is the tight integration of the viral life cycle with the host's cellular machinery. However, the reliance of the virus on the host cell replication machinery is also an opportunity for therapeutic targeting, as successful entry- and exit-inhibitors have demonstrated. An understanding of the extracellular and intracellular structure and dynamics of the virion - as well as of the entry and exit pathways in host and vector cells - is therefore crucial to the advancement of novel antivirals. In recent years, advances in computing architecture and algorithms have begun to allow us to use simulations to study the structure and dynamics of viral ultrastructures at various stages of their life cycle in atomistic or near-atomistic detail. In this review, we outline specific challenges and solutions that have emerged to allow for structurally detailed modelling of viruses in silico. We focus on the history and state of the art of atomistic and coarse-grained approaches to simulate the dynamics of the large, macromolecular structures associated with viral infection, and on their usefulness in explaining and expanding upon experimental data. We discuss the types of interactions that need to be modeled to describe major components of the virus particle and advances in modelling techniques that allow for the treatment of these systems, highlighting recent key simulation studies.
病毒病原体是人类发病和死亡的重要根源，对全球社会和经济有着重大影响。用药物靶向这些病原体所固有的挑战之一是病毒生命周期与宿主细胞机制紧密结合。然而，正如成功的进入和退出抑制剂所表明的那样，病毒对宿主细胞复制机制的依赖也是治疗靶向的一个机会。因此，了解病毒粒子的细胞外和细胞内结构及动力学，以及宿主和载体细胞中的进入和退出途径，对于新型抗病毒药物的研发至关重要。近年来，计算架构和算法的进步已开始使我们能够利用模拟，以原子或近原子细节研究病毒在其生命周期各个阶段的超微结构的结构和动力学。在本综述中，我们概述了为在计算机上对病毒进行结构细节建模而出现的具体挑战和解决方案。我们重点介绍了用于模拟与病毒感染相关的大型大分子结构动力学的原子和粗粒度方法的历史和现状，以及它们在解释和扩展实验数据方面的实用性。我们讨论了为描述病毒粒子主要成分而需要建模的相互作用类型，以及用于处理这些系统的建模技术的进展，并重点介绍了近期的关键模拟研究。
