Department of Biology, University of Maryland, College Park, Maryland 20742, USA.
Proteins. 2010 Mar;78(4):932-49. doi: 10.1002/prot.22618.
Most crystallized homo-oligomeric ion channels are highly symmetric, which dramatically decreases conformational space and facilitates building homology models (HMs). However, in molecular dynamics (MD) simulations channels deviate from ideal symmetry and accumulate thermal defects, which complicate the refinement of HMs using MD. In this work we evaluate the ability of symmetry constrained MD simulations to improve HMs accuracy, using an approach conceptually similar to Critical Assessment of techniques for protein Structure Prediction (CASP) competition: build HMs of channels with known structure and evaluate the efficiency of proposed methods in improving HMs accuracy (measured as deviation from experimental structure). Results indicate that unrestrained MD does not improve the accuracy of HMs, instantaneous symmetrization improves accuracy but not stability of HMs during subsequent unrestrained MD, while gradually imposing symmetry constraints improves both accuracy (by 5-50%) and stability of HMs. Moreover, accuracy and stability are strongly correlated, making stability a reliable criterion in predicting the accuracy of new HMs. Proteins 2010. (c) 2009 Wiley-Liss, Inc.
大多数结晶的同型寡聚离子通道具有高度的对称性，这极大地减少了构象空间，便于构建同源模型（HM）。然而，在分子动力学（MD）模拟中，通道偏离理想的对称性并积累热缺陷，这使得使用 MD 对 HM 进行精修复杂化。在这项工作中，我们使用与蛋白质结构预测技术评估（CASP）竞赛中概念上相似的方法，评估了对称约束 MD 模拟在提高 HM 准确性方面的能力：构建具有已知结构的通道的 HM，并评估所提出方法在提高 HM 准确性方面的效率（以与实验结构的偏差来衡量）。结果表明，不受约束的 MD 并不能提高 HM 的准确性，瞬时对称化提高了 HM 的准确性，但不能提高随后不受约束的 MD 期间 HM 的稳定性，而逐渐施加对称约束则提高了 HM 的准确性（提高 5-50%）和稳定性。此外，准确性和稳定性密切相关，使得稳定性成为预测新 HM 准确性的可靠标准。 蛋白质 2010. （c）2009 年 Wiley-Liss，Inc.
