Van't Hoff Institute for Molecular Sciences, Universiteit van Amsterdam, Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands.
Faraday Discuss. 2010;144:127-41; discussion 203-22, 467-81. doi: 10.1039/b901608b.
Collagen-silk-collagen triblock polypeptides can self-assemble at low pH into nanometer thin fibers with a length in the order of micrometers. Previously we predicted, via all-atom simulations, the structure of the folded silk domain to be a beta-roll. In this work we develop a simple coarse-grained model of the silk domain to enable a numerical study of the fiber's properties and formation on a larger length and time scale. As an initial coarse-grained model for the fiber forming protein we chose the model of Brown et al., Proc. Natl. Acad Sci. U.S.A., 2003, 100, 10712-10717. We adapted this model, and optimized its parameters to reproduce the all-atom molecular dynamics simulation structural data. The unknown strength of the attraction between the beads representing the residues is optimized by computing the Potential of Mean Force for unfolding a strand of the beta-roll, using non-equilibrium steered MD simulations in combination with the Jarzynski relation. Using these optimized parameters we observed spontaneous folding of a short peptide. The coarse-grained beta-roll, as well as a much larger stack (a fiber) of beta-rolls, were found to be stable. Moreover, the predicted fiber persistence length is in agreement with experiment. The efficacy of the mapping of a coarse-grained system onto an all-atom simulation is discussed. The approach opens the way for large-scale simulations of fibers, based on molecular structure, and allows investigation of their nucleation, growth, cross-linking mechanism, network dynamics, and rheology.
胶原-丝胶-胶原三嵌段多肽在低 pH 值下可以自组装成长度在微米级的纳米级薄纤维。之前，我们通过全原子模拟预测折叠丝域的结构为β-滚。在这项工作中，我们开发了一个简单的粗粒化模型来模拟丝域，以在更大的长度和时间尺度上研究纤维的性质和形成。作为形成纤维的蛋白质的初始粗粒化模型，我们选择了 Brown 等人的模型，Proc. Natl. Acad. Sci. U.S.A.，2003，100，10712-10717。我们改编了这个模型，并优化了它的参数，以再现全原子分子动力学模拟的结构数据。通过使用非平衡引导 MD 模拟结合 Jarzynski 关系计算展开β-滚链的平均力势来优化代表残基的珠子之间的吸引力强度。使用这些优化的参数，我们观察到短肽的自发折叠。粗粒化的β-滚，以及更大的β-滚堆叠（纤维），都被发现是稳定的。此外，预测的纤维持久长度与实验相符。讨论了将粗粒化系统映射到全原子模拟的有效性。这种方法为基于分子结构的纤维的大规模模拟开辟了道路，并允许研究它们的成核、生长、交联机制、网络动力学和流变学。
