Ingenuity in performing replica permutation: How to order the state labels for improving sampling efficiency.

In the replica-permutation method, an advanced version of the replica-exchange method, all combinations of replicas and parameters are considered for parameter permutation, and a list of all the combinations is prepared. Here, we report that the temperature transition probability depends on how the list is created, especially in replica permutation with solute tempering (RPST). We found that the transition probabilities decrease at large replica indices when the combinations are sequentially assigned to the state labels as in the originally proposed list. To solve this problem, we propose to modify the list by randomly assigning the combinations to the state labels. We performed molecular dynamics simulations of amyloid-ß(16-22) peptides using RPST with the "randomly assigned" list (RPST-RA) and RPST with the "sequentially assigned" list (RPST-SA). The results show the decreases in the transition probabilities in RPST-SA are eliminated, and the sampling efficiency is improved in RPST-RA.

Molecular dynamics simulations for the study of chromatin biology.

The organization of Eukaryotic DNA into chromatin has profound implications for the processing of genetic information. In the past years, molecular dynamics (MD) simulations proved to be a powerful tool to investigate the mechanistic basis of chromatin biology. We review recent all-atom and coarse-grained MD studies revealing how the structure and dynamics of chromatin underlie its biological functions. We describe the latest method developments; the structural fluctuations of nucleosomes and the various factors affecting them; the organization of chromatin fibers, with particular emphasis on its liquid-like character; the interactions and dynamics of transcription factors on chromatin; and how chromatin organization is modulated by molecular motors acting on DNA.

Dimerization of α-Synuclein Fragments Studied by Isothermal-Isobaric Replica-Permutation Molecular Dynamics Simulation.

Aggregates and fibrils of intrinsically disordered α-synuclein are associated with Parkinson's disease. Within a non-amyloid ß component (NAC) spanning from the 61st to the 95th residue of α-synuclein, an 11-residue segment called NACore (68GAVVTGVTAVA78) is an essential region for both fibril formation and cytotoxicity. Although NACore peptides alone are known to form aggregates and amyloid fibrils, the mechanisms of aggregation and fibrillation remain unknown. This study investigated the dimerization process of NACore peptides as the initial stage of the aggregation and fibrillation processes. We performed an isothermal-isobaric replica-permutation molecular dynamics simulation, which is one of the efficient sampling methods, for the two NACore peptides in explicit water over 96 µs. The simulation succeeded in sampling a variety of dimer structures. An analysis of secondary structure revealed that most of the NACore dimers form intermolecular ß-bridges. In particular, more antiparallel ß-bridges were observed than parallel ß-bridges. We also found that intramolecular secondary structures such as α-helix and antiparallel ß-bridge are stabilized in the pre-dimer state. However, we identified that the intermolecular ß-bridges tend to form directly between residues with no specific structure rather than via the intramolecular ß-bridges. This is because the NACore peptides still have a low propensity to form the intramolecular secondary structures even though they are stabilized in the pre-dimer state.

Replica sub-permutation method for molecular dynamics and monte carlo simulations.

We propose an improvement of the replica-exchange and replica-permutation methods, which we call the replica sub-permutation method (RSPM). Instead of considering all permutations, this method uses a new algorithm referred to as sub-permutation to perform parameter transition. The RSPM succeeds in reducing the number of combinations between replicas and parameters without the loss of sampling efficiency. For comparison, we applied the replica sub-permutation, replica-permutation, and replica-exchange methods to a ß-hairpin mini protein, chignolin, in explicit water. We calculated the transition ratio and number of tunneling events in the parameter space, the number of folding-unfolding events, the autocorrelation function, and the autocorrelation time as measures of sampling efficiency. The results indicate that among the three methods, the proposed RSPM is the most efficient in both parameter and conformational spaces. © 2019 Wiley Periodicals, Inc.

Molecular simulations by generalized-ensemble algorithms in isothermal-isobaric ensemble.

Generalized-ensemble algorithms are powerful techniques for investigating biomolecules such as protein, DNA, lipid membrane, and glycan. The generalized-ensemble algorithms were originally developed in the canonical ensemble. On the other hand, not only temperature but also pressure is controlled in experiments. Additionally, pressure is used as perturbation to study relationship between function and structure of biomolecules. For this reason, it is important to perform efficient conformation sampling based on the isothermal-isobaric ensemble. In this article, we review a series of the generalized-ensemble algorithms in the isothermal-isobaric ensemble: multibaric-multithermal, pressure- and temperature-simulated tempering, replica-exchange, and replica-permutation methods. These methods achieve more efficient simulation than the conventional isothermal-isobaric simulation. Furthermore, the isothermal-isobaric generalized-ensemble simulation samples conformations of biomolecules from wider range of temperature and pressure. Thus, we can estimate physical quantities more accurately at any temperature and pressure values. The applications to the biomolecular system are also presented.

Development of isothermal-isobaric replica-permutation method for molecular dynamics and Monte Carlo simulations and its application to reveal temperature and pressure dependence of folded, misfolded, and unfolded states of chignolin.

We developed a two-dimensional replica-permutation molecular dynamics method in the isothermal-isobaric ensemble. The replica-permutation method is a better alternative to the replica-exchange method. It was originally developed in the canonical ensemble. This method employs the Suwa-Todo algorithm, instead of the Metropolis algorithm, to perform permutations of temperatures and pressures among more than two replicas so that the rejection ratio can be minimized. We showed that the isothermal-isobaric replica-permutation method performs better sampling efficiency than the isothermal-isobaric replica-exchange method and infinite swapping method. We applied this method to a ß-hairpin mini protein, chignolin. In this simulation, we observed not only the folded state but also the misfolded state. We calculated the temperature and pressure dependence of the fractions on the folded, misfolded, and unfolded states. Differences in partial molar enthalpy, internal energy, entropy, partial molar volume, and heat capacity were also determined and agreed well with experimental data. We observed a new phenomenon that misfolded chignolin becomes more stable under high-pressure conditions. We also revealed this mechanism of the stability as follows: TYR2 and TRP9 side chains cover the hydrogen bonds that form a ß-hairpin structure. The hydrogen bonds are protected from the water molecules that approach the protein as the pressure increases.