Department of Biological Physical Chemistry, Rocasolano Institute of Physical Chemistry, CSIC, Serrano 119, 28006 Madrid, Spain.
Centro de Biología Molecular "Severo Ochoa," CSIC-UAM, Cantoblanco, 28049 Madrid, Spain.
J Chem Inf Model. 2022 Sep 26;62(18):4561-4568. doi: 10.1021/acs.jcim.2c00870. Epub 2022 Sep 13.
We propose and validate a novel method to efficiently explore local protein loop conformations based on a new formalism for constrained normal mode analysis (NMA) in internal coordinates. The manifold of possible loop configurations imposed by the position and orientation of the fixed loop ends is reduced to an orthogonal set of motions (or modes) encoding concerted rotations of all the backbone dihedral angles. We validate the sampling power on a set of protein loops with highly variable experimental structures and demonstrate that our approach can efficiently explore the conformational space of closed loops. We also show an acceptable resemblance of the ensembles around equilibrium conformations generated by long molecular simulations and constrained NMA on a set of exposed and diverse loops. In comparison with other methods, the main advantage is the lack of restrictions on the number of dihedrals that can be altered simultaneously. Furthermore, the method is computationally efficient since it only requires the diagonalization of a tiny matrix, and the modes of motions are energetically contextualized by the elastic network model, which includes both the loop and the neighboring residues.
我们提出并验证了一种新的方法，基于内部坐标的约束模态分析（NMA）的新形式，可以有效地探索局部蛋白质环构象。由固定环端的位置和方向施加的可能环构象流形被简化为一组正交运动（或模式），编码所有骨架二面角的协同旋转。我们在一组具有高度可变实验结构的蛋白质环上验证了采样能力，并证明我们的方法可以有效地探索闭环的构象空间。我们还展示了在一组暴露和多样化的环上，通过长分子模拟和约束 NMA 生成的平衡构象周围的集合之间可接受的相似性。与其他方法相比，主要优点是可以同时改变的二面角数量没有限制。此外，该方法计算效率高，因为它只需要对一个小矩阵进行对角化，并且运动模式通过包括环和相邻残基的弹性网络模型进行能量上下文化。
