Petukh Marharyta, Kucukkal Tugba G, Alexov Emil
Department of Physics, Clemson University, Clemson, SC 29642, USA.
Hum Mutat. 2015 May;36(5):524-534. doi: 10.1002/humu.22770. Epub 2015 Apr 6.
Statistical analysis was carried out on large set of naturally occurring human amino acid variations, and it was demonstrated that there is a preference for some amino acid substitutions to be associated with diseases. At an amino acid sequence level, it was shown that the disease-causing variants frequently involve drastic changes in amino acid physicochemical properties of proteins such as charge, hydrophobicity, and geometry. Structural analysis of variants involved in diseases and being frequently observed in human population showed similar trends: disease-causing variants tend to cause more changes in hydrogen bond network and salt bridges as compared with harmless amino acid mutations. Analysis of thermodynamics data reported in the literature, both experimental and computational, indicated that disease-causing variants tend to destabilize proteins and their interactions, which prompted us to investigate the effects of amino acid mutations on large databases of experimentally measured energy changes in unrelated proteins. Although the experimental datasets were linked neither to diseases nor exclusory to human proteins, the observed trends were the same: amino acid mutations tend to destabilize proteins and their interactions. Having in mind that structural and thermodynamics properties are interrelated, it is pointed out that any large change in any of them is anticipated to cause a disease.
对大量自然发生的人类氨基酸变异进行了统计分析，结果表明某些氨基酸替代与疾病相关存在偏好性。在氨基酸序列水平上，研究表明致病变异常常涉及蛋白质氨基酸物理化学性质的剧烈变化，如电荷、疏水性和几何形状。对疾病相关且在人群中频繁观察到的变异进行结构分析显示出类似趋势：与无害的氨基酸突变相比，致病变异往往会导致氢键网络和盐桥发生更多变化。对文献中报道的热力学数据（包括实验数据和计算数据）进行分析表明，致病变异往往会使蛋白质及其相互作用不稳定，这促使我们研究氨基酸突变对大量无关蛋白质实验测量能量变化数据库的影响。尽管实验数据集既未与疾病相关联，也并非仅限于人类蛋白质，但观察到的趋势是相同的：氨基酸突变往往会使蛋白质及其相互作用不稳定。考虑到结构和热力学性质是相互关联的，有人指出其中任何一个的任何大变化都预计会导致疾病。
