Barcelona Supercomputing Center (BSC), 08034 Barcelona, Spain.
Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, 08035 Barcelona; Spain.
Int J Mol Sci. 2019 Mar 29;20(7):1583. doi: 10.3390/ijms20071583.
One of the known potential effects of disease-causing amino acid substitutions in proteins is to modulate protein-protein interactions (PPIs). To interpret such variants at the molecular level and to obtain useful information for prediction purposes, it is important to determine whether they are located at protein-protein interfaces, which are composed of two main regions, core and rim, with different evolutionary conservation and physicochemical properties. Here we have performed a structural, energetics and computational analysis of interactions between proteins hosting mutations related to diseases detected in newborn screening. Interface residues were classified as core or rim, showing that the core residues contribute the most to the binding free energy of the PPI. Disease-causing variants are more likely to occur at the interface core region rather than at the interface rim ( < 0.0001). In contrast, neutral variants are more often found at the interface rim or at the non-interacting surface rather than at the interface core region. We also found that arginine, tryptophan, and tyrosine are over-represented among mutated residues leading to disease. These results can enhance our understanding of disease at molecular level and thus contribute towards personalized medicine by helping clinicians to provide adequate diagnosis and treatments.
已知致病氨基酸替换会影响蛋白质-蛋白质相互作用（PPIs）。为了在分子水平上解释这些变体，并为预测目的获取有用信息，确定它们是否位于由两个主要区域组成的蛋白质-蛋白质界面上非常重要，这两个区域分别为核心区和边缘区，具有不同的进化保守性和物理化学性质。在这里，我们对与新生儿筛查中发现的疾病相关的突变体宿主蛋白之间的相互作用进行了结构、能量和计算分析。将界面残基分类为核心或边缘，结果表明核心残基对 PPI 的结合自由能贡献最大。致病变体更可能发生在界面核心区域，而不是界面边缘区域（<0.0001）。相比之下，中性变体更常发生在界面边缘或非相互作用表面，而不是界面核心区域。我们还发现，导致疾病的突变残基中精氨酸、色氨酸和酪氨酸过度表达。这些结果可以增强我们对疾病的分子水平的理解，从而通过帮助临床医生提供适当的诊断和治疗来促进个性化医疗。
