Yildiz Muslum, Kocak Abdulkadir
Department of Molecular Biology and Genetics, Gebze Technical University, Kocaeli, Turkey.
Department of Chemistry, Gebze Technical University, Kocaeli, Turkey.
J Comput Biol. 2019 Sep;26(9):962-974. doi: 10.1089/cmb.2018.0163. Epub 2018 Dec 20.
Norovirus is the causing agent of acute gastroenteritis disease globally. Efforts in developing therapeutics against virus infection mostly fail due to emergence of drug resistance that is a consequence of presence of high mutation rates in virus genome during virus' life cycle. In this study, we computationally analyzed the affinity of a drug target, wild type VP1 envelope protein and its three variants to a therapeutic antibody FAB5I2. We have found that mutations break important hydrogen bonds and cause high fluctuations in residues that form VP1-FAB5I2 complex interface. In addition to changes in dynamics, we also revealed that the affinity of FAB5I2 to VP1 protein drops significantly upon mutations in terms of relative binding free energy.
诺如病毒是全球急性肠胃炎疾病的致病原。开发针对病毒感染的治疗方法大多失败，原因是出现了耐药性，这是病毒生命周期中病毒基因组高突变率导致的结果。在本研究中，我们通过计算分析了一种药物靶点、野生型VP1包膜蛋白及其三种变体与治疗性抗体FAB5I2的亲和力。我们发现，突变破坏了重要的氢键，并导致形成VP1 - FAB5I2复合界面的残基出现高度波动。除了动力学变化外，我们还发现，就相对结合自由能而言，FAB5I2与VP1蛋白的亲和力在发生突变后显著下降。
