Azadi Sh, Tafazzoli-Shadpour M, Omidvar R
Faculty of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran.
Mol Biol (Mosk). 2018 Sep-Oct;52(5):836-845. doi: 10.1134/S002689841805004X.
E-cadherin is a member of the cadherin family that plays a key role in the formation of cell-cell adhesion among epithelial tissues. Point mutations are one of the structural abnormalities of E-cadherin in human carcinomas. Such abnormalities can alter mechanical properties of proteins that play an important role in their biological activities. To determine the impact of point mutations on protein mechanical properties, the second fragment of extracellular domain of E-cadherin was modeled using steered molecular dynamics simulations. The molecular dynamics modeling included application of tensile forces in both constant velocity and constant force modes to examine the effects of Met282 to He and Asn315 to Ser mutations on mechanical behavior of protein structure. The stabilities of the wild type and mutant structures were also obtained by the protein design foldX algorithm. Results confirmed the lower stability of the mutant domains compared to the wild type. The mutated proteins displayed softer behavior than the reference protein and their stiffness decreased by up to 34%. Our findings suggest that local changes in molecular structure due to mutations may lead to noticeable alterations in mechanical properties within the entire domain. Since the function of protein is related to its structure, these changes may influence the function of the protein.
E-钙黏蛋白是钙黏蛋白家族的一员，在上皮组织中细胞间黏附的形成过程中发挥关键作用。点突变是人类癌症中E-钙黏蛋白的结构异常之一。此类异常可改变蛋白质的机械性能，而这些性能在其生物学活性中起着重要作用。为了确定点突变对蛋白质机械性能的影响，利用引导分子动力学模拟对E-钙黏蛋白细胞外结构域的第二个片段进行了建模。分子动力学建模包括在恒速和恒力模式下施加拉力，以研究Met282突变为He以及Asn315突变为Ser对蛋白质结构机械行为的影响。野生型和突变型结构的稳定性也通过蛋白质设计foldX算法获得。结果证实，与野生型相比，突变结构域的稳定性较低。突变蛋白表现出比参考蛋白更软的行为，其刚度降低了34%。我们的研究结果表明，突变导致的分子结构局部变化可能会导致整个结构域内机械性能发生显著改变。由于蛋白质的功能与其结构相关，这些变化可能会影响蛋白质的功能。
