Molecular dynamics simulation is a fruitful tool for investigating the structural stability, dynamics, and functions of biopolymers at an atomic level. In recent years, simulations can be performed on time scales of the order of milliseconds using specialpurpose systems. Since the most stable structure, as well as meta-stable structures and intermediate structures, is included in trajectories in long simulations, it is necessary to develop analysis methods for extracting them from trajectories of simulations. For these structures, methods for evaluating the stabilities, including the solvent effect, are also needed. We have developed relaxation mode analysis to investigate dynamics and kinetics of simulations based on statistical mechanics. We have also applied the three-dimensional reference interaction site model theory to investigate stabilities with solvent effects. In this paper, we review the results for designing amino-acid substitution of the 10-residue peptide, chignolin, to stabilize the misfolded structure using these developed analysis methods.It is important to develop analysis methods for molecular simulations of protein systems. We have developed relaxation mode analysis to investigate dynamics and kinetics of simulations. We also have applied the three-dimensional reference interaction site model theory to investigate stability with solvent effects. Here, we review the results for designing amino-acid substitution of 10-residue peptide, chignolin, to stabilize the misfolded structure using these analysis methods based on statistical mechanics.
Background of mode decomposition methods for protein simulationsAs longer and larger MD simulations are performed, it has become increasingly important to develop methods to extract the "essential" information from the trajectory. The reduction in the large number of degrees of freedom of coordinates to a few collective ones is an active field of theo retical research. In NMA, the normal modes near the minimum potential energy of the protein molecule are obtained [3,24,25]. LMA investigates modes around a minimumenergy state, including the water effect [4,6,26,27]. An elastic network model and a Gaussian network model approximately calculate normal modes with large amplitudes by using the harmonic potential of coarse-grained models [28][29][30][31][32]. This method extracts collective modes with large amplitudes for large protein systems like viruses, because such proteins have rigid-like motions [33]. PCA, also called quasiharmonic analysis or the essential dynamics method [6,7,[34][35][36][37][38], is one of the most popular methods for analyzing the structural fluctuations around the average structure. The modes with large structure fluctuations are extracted and are considered cooperative movement, and the relation of these fluctuations with function has been widely examined. The obtained modes are also used as the axis of the free-energy surface. The JAM model was introduced for treating multiple-hierarchy free-energy landscapes [9]. They divided protei...
