Sinner Claude, Lutz Benjamin, Verma Abhinav, Schug Alexander
Steinbuch Centre for Computing, Karlsruhe Institute of Technology, Karlsruhe, Germany.
J Chem Phys. 2015 Dec 28;143(24):243154. doi: 10.1063/1.4938172.
The full characterization of protein folding is a remarkable long-standing challenge both for experiment and simulation. Working towards a complete understanding of this process, one needs to cover the full diversity of existing folds and identify the general principles driving the process. Here, we want to understand and quantify the diversity in folding routes for a large and representative set of protein topologies covering the full range from all alpha helical topologies towards beta barrels guided by the key question: Does the majority of the observed routes contribute to the folding process or only a particular route? We identified a set of two-state folders among non-homologous proteins with a sequence length of 40-120 residues. For each of these proteins, we ran native-structure based simulations both with homogeneous and heterogeneous contact potentials. For each protein, we simulated dozens of folding transitions in continuous uninterrupted simulations and constructed a large database of kinetic parameters. We investigate folding routes by tracking the formation of tertiary structure interfaces and discuss whether a single specific route exists for a topology or if all routes are equiprobable. These results permit us to characterize the complete folding space for small proteins in terms of folding barrier ΔG(‡), number of routes, and the route specificity RT.
蛋白质折叠的全面表征对实验和模拟来说都是一项长期存在的重大挑战。为了全面理解这一过程，人们需要涵盖现有折叠的全部多样性，并确定驱动该过程的一般原则。在此，我们希望理解并量化一系列具有代表性的大型蛋白质拓扑结构在折叠路径上的多样性，这些拓扑结构涵盖了从所有α螺旋拓扑到β桶的整个范围，我们以关键问题为导向：观察到的大多数路径对折叠过程有贡献，还是只有特定的一条路径？我们在长度为40 - 120个残基的非同源蛋白质中鉴定出一组两态折叠蛋白。对于这些蛋白质中的每一个，我们使用均匀和非均匀接触势进行基于天然结构的模拟。对于每种蛋白质，我们在连续不间断的模拟中模拟了数十次折叠转变，并构建了一个大型动力学参数数据库。我们通过追踪三级结构界面的形成来研究折叠路径，并讨论对于一种拓扑结构是否存在单一特定路径，或者所有路径是否具有同等可能性。这些结果使我们能够根据折叠势垒ΔG(‡)、路径数量和路径特异性RT来表征小蛋白质的完整折叠空间。
