Stacklies Wolfram, Vega M Cristina, Wilmanns Matthias, Gräter Frauke
CAS-MPG Partner Institute for Computational Biology, Shanghai, People's Republic of China.
PLoS Comput Biol. 2009 Mar;5(3):e1000306. doi: 10.1371/journal.pcbi.1000306. Epub 2009 Mar 13.
The role of mechanical force in cellular processes is increasingly revealed by single molecule experiments and simulations of force-induced transitions in proteins. How the applied force propagates within proteins determines their mechanical behavior yet remains largely unknown. We present a new method based on molecular dynamics simulations to disclose the distribution of strain in protein structures, here for the newly determined high-resolution crystal structure of I27, a titin immunoglobulin (IG) domain. We obtain a sparse, spatially connected, and highly anisotropic mechanical network. This allows us to detect load-bearing motifs composed of interstrand hydrogen bonds and hydrophobic core interactions, including parts distal to the site to which force was applied. The role of the force distribution pattern for mechanical stability is tested by in silico unfolding of I27 mutants. We then compare the observed force pattern to the sparse network of coevolved residues found in this family. We find a remarkable overlap, suggesting the force distribution to reflect constraints for the evolutionary design of mechanical resistance in the IG family. The force distribution analysis provides a molecular interpretation of coevolution and opens the road to the study of the mechanism of signal propagation in proteins in general.
单分子实验以及对蛋白质中力诱导转变的模拟越来越多地揭示了机械力在细胞过程中的作用。施加的力如何在蛋白质内部传播决定了它们的力学行为，但在很大程度上仍不清楚。我们提出了一种基于分子动力学模拟的新方法，以揭示蛋白质结构中的应变分布，这里以肌联蛋白免疫球蛋白（IG）结构域I27新确定的高分辨率晶体结构为例。我们获得了一个稀疏、空间相连且高度各向异性的力学网络。这使我们能够检测由链间氢键和疏水核心相互作用组成的承重基序，包括施力部位远端的部分。通过对I27突变体进行计算机模拟解折叠，测试了力分布模式对机械稳定性的作用。然后，我们将观察到的力模式与该家族中共同进化残基的稀疏网络进行比较。我们发现了显著的重叠，这表明力分布反映了IG家族中机械抗性进化设计的限制。力分布分析为共同进化提供了分子解释，并为一般蛋白质中信号传播机制的研究开辟了道路。
