A study on protein conformational transitions by Monte Carlo simulations

Abstract

Exploration of conformational transitions between two different conformational states of proteins reveals significant information about their action mechanism and function. In this thesis, the recently developed anisotropic network model-Monte Carlo (ANM-MC) and targeted Monte Carlo (TMC) simulations are applied between two experimentally determined distinct conformations (initial/target) of 12 proteins with different sizes, number of chains, domains and motion types. The objective is to obtain a database of conformational transitions in forward-reverse directions of apo (free) to complex transitions. In ANM-MC, collective modes ontained from ANM are combined with the MC simulation approach. In TMC, the initial structure is forced towards the target structure without using collective modes. the simulation parameters were modified to perform better energy minimization and an automated version of the algorithm was developed to reduce the simulation time. The root mean-square deviation (RMSD) valuse between the initial and target states of the proteins studied fall between 4.1 and 15.6 A. As a result of TMC, all proteins approach the target within RMSD of 0.4 A. On the other hand, The RMSD values between the predicted final structure in the forward ANM-MC and the target structure very between 1.4 and 3.9A, whereas it varies between 1.8 and 4.7A in the reverse ANM-MC (excluding the unsuccessful case of diphtheria toxin). High initial overlap values between the selected modes and the target direction derive the conformations more to the target state. In general, the proteins with a hinge bending motion between two domains exhibit the most successful results and high overlap values. The most selected ANM modes in the initial stages of the simulation are the slowest five modes. Contact maps of the corresponding intermediates (snapshots) and the final structure are also analyzed. In all cases, the final structure is very similar to the target structure in terms of newly formed contacts and overall three-dimensional conformation.