Maisuradze Gia G, Liwo Adam, Senet Patrick, Scheraga Harold A
Baker Laboratory of Chemistry and Chemical Biology, Cornell University Ithaca, New York 14853-1301.
J Chem Theory Comput. 2013 Jul 9;9(7):2907-2921. doi: 10.1021/ct4001558.
It is of interest to know whether local fluctuations in a polypeptide chain play any role in the mechanism by which the chain folds to the native structure of a protein. This question is addressed by analyzing folding and non-folding trajectories of a protein; as an example, the analysis is applied to the 37-residue triple β-strand WW domain from the Formin binding protein 28 (FBP28) (PDB ID: 1E0L). Molecular dynamics (MD) trajectories were generated with the coarse-grained united-residue force field, and one- and two-dimensional free-energy landscapes (FELs) along the backbone virtual-bond angle θ and backbone virtual-bond-dihedral angle γ of each residue, and principal components, respectively, were analyzed. The key residues involved in the folding of the FBP28 WW domain are elucidated by this analysis. The correlations between local and global motions are found. It is shown that most of the residues in the folding trajectories of the system studied here move in a concerted fashion, following the dynamics of the whole system. This demonstrates how the choice of a pathway has to involve concerted movements in order for this protein to fold. This finding also sheds light on the effectiveness of principal component analysis (PCA) for the description of the folding dynamics of the system studied. It is demonstrated that the FEL along the PCs, computed by considering only several critically-placed residues, can correctly describe the folding dynamics.
了解多肽链中的局部波动是否在该链折叠成蛋白质天然结构的机制中发挥任何作用是很有意义的。通过分析蛋白质的折叠和非折叠轨迹来解决这个问题；例如，将该分析应用于来自formin结合蛋白28（FBP28）的37个残基的三股β链WW结构域（PDB ID：1E0L）。使用粗粒度的联合残基力场生成分子动力学（MD）轨迹，并分别沿着每个残基的主链虚拟键角θ和主链虚拟键二面角γ以及主成分分析一维和二维自由能景观（FEL）。通过该分析阐明了FBP28 WW结构域折叠过程中涉及的关键残基。发现了局部运动和全局运动之间的相关性。结果表明，这里研究的系统折叠轨迹中的大多数残基以协同方式移动，遵循整个系统的动力学。这表明为了使这种蛋白质折叠，途径的选择必须涉及协同运动。这一发现也揭示了主成分分析（PCA）在描述所研究系统的折叠动力学方面的有效性。结果表明，通过仅考虑几个关键位置的残基计算得到的沿主成分的自由能景观可以正确描述折叠动力学。
