Local Normal Mode Analysis for Fast Loop Conformational Sampling

Abstract

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.

Loop Dynamics and Conformational Flexibility in Dengue Serine Protease Activity: Noninvasive Perturbation by Solvent Exchange

“…Principal components analysis (PCA) is a useful tool for analyzing the trajectories of an MD simulation to draw the major modes in the motion of the molecule. These major motions correspond to the correlated vibrational modes or collective motions of groups of atoms in the normal mode analysis. , The VMD timeline tools (normal mode wizard and the ProDy interface) were used to generate the mobility plots summarizing the direction and amplitude of the major motions along the simulation trajectories by PCA. Porcupine diagrams of the eigenvalues projected on the protein structures and the residue-wise mobility plots for the respective systems (protein in water, DMSO, and water–DMSO mixtures) were generated with VMD.…”