We propose a new algorithm for obtaining proton titration curves of ionizable residues. The algorithm is a pH replica-exchange method (PHREM) which is based on the constant pH algorithm of Mongan et al. [1]. In the original replica-exchange method, simulations of different replicas are performed at different temperature, and the temperatures are exchanged between the replicas. In our pH replica-exchange method, simulations of different replicas are performed at different pH values, and the pHs are exchanged between the replicas. The PHREM was applied to a blocked amino acid and to two protein systems (Snake Cardiotoxin and Turkey Ovomucoid Third Domain), in conjunction with a generalized Born implicit solvent. The performance and accuracy of this algorithm and the original constant pH method (PHMD) were compared. For a single set of simulations at different pHs, the use of PHREM yields more accurate Hill coefficients of titratable residues. By performing multiple sets of constant pH simulations started with different initial states the accuracy of predicted pKa values and Hill coefficients obtained with PHREM and PHMD methods becomes comparable. However, the PHREM algorithm exhibits better samplings of the protonation states of titratable residues and less scatter of the titration points and thus better precision of measured pKa values and Hill coefficients. In addition, PHREM exhibits faster convergence of individual simulations than the original constant pH algorithm.

We propose a new method for molecular dynamics and Monte Carlo simulations, which is referred to as the replica-permutation method (RPM), to realize more efficient sampling than the replicaexchange method (REM). In RPM not only exchanges between two replicas but also permutations among more than two replicas are performed. Furthermore, instead of the Metropolis algorithm, the Suwa-Todo algorithm is employed for replica-permutation trials to minimize its rejection ratio.We applied RPM to particles in a double-well potential energy, Met-enkephalin in vacuum, and a C-peptide analog of ribonuclease A in explicit water. For a comparison purposes, replica-exchange molecular dynamics simulations were also performed. As a result, RPM sampled not only the temperature space but also the conformational space more efficiently than REM for all systems.From our simulations of C-peptide, we obtained the α-helix structure with salt-bridges between Gly2 and Arg10 which is known in experiments. Calculating its free-energy landscape, the folding pathway was revealed from an extended structure to the α-helix structure with the salt-bridges.We found that the folding pathway consists of the two steps: The first step is the "salt-bridge formation step", and the second step is the "α-helix formation step". * Electronic address: itoh@ims.ac.jp † Electronic address: hokumura@ims.ac.jp

We describe the disruption of amyloid fibrils of Alzheimer's amyloid-β peptides by ultrasonic cavitation. For this purpose, we performed nonequilibrium all-atom molecular dynamics simulations with sinusoidal pressure and visualized the process with movies. When the pressure is negative, a bubble is formed, usually at hydrophobic residues in the transmembrane region. Most β-strands maintain their secondary structures in the bubble. When the pressure becomes positive, the bubble collapses, and water molecules crash against the hydrophilic residues in the nontransmembrane region to disrupt the amyloid. Shorter amyloids require longer sonication times for disruption because they do not have enough hydrophobic residues to serve as a nucleus to form a bubble. These results agree with experiments in which monodispersed amyloid fibrils were obtained by ultrasonication.

We propose the Hamiltonian replica-permutation method (RPM) (or multidimensional RPM) for molecular dynamics and Monte Carlo simulations, in which parameters in the Hamiltonian are permuted among more than two replicas with the Suwa-Todo algorithm. We apply the Coulomb RPM, which is one of realization of the Hamiltonian RPM, to an alanine dipeptide and to two amyloid-β(29-42) molecules. The Hamiltonian RPM realizes more efficient sampling than the Hamiltonian replica-exchange method. We illustrate the protein misfolding funnel of amyloid-β(29-42) and reveal its dimerization pathways.

The authors propose explicit symplectic integrators of molecular dynamics (MD) algorithms for rigid-body molecules in the canonical and isobaric-isothermal ensembles. They also present a symplectic algorithm in the constant normal pressure and lateral surface area ensemble and that combined with the Parrinello-Rahman algorithm. Employing the symplectic integrators for MD algorithms, there is a conserved quantity which is close to Hamiltonian. Therefore, they can perform a MD simulation more stably than by conventional nonsymplectic algorithms. They applied this algorithm to a TIP3P pure water system at 300 K and compared the time evolution of the Hamiltonian with those by the nonsymplectic algorithms. They found that the Hamiltonian was conserved well by the symplectic algorithm even for a time step of 4 fs. This time step is longer than typical values of 0.5-2 fs which are used by the conventional nonsymplectic algorithms.

bleeding complications among patients with AF, compared with use of vitamin K antagonists. 2-5 Review of real-world registries in Japan has indicated the incidence rate of stroke with DOAC therapy to be similar to that with warfarin but with a lower risk for major bleeding events for DOACs A trial fibrillation (AF) is the most common arrhythmia in elderly individuals, currently affecting approximately 0.6% of the Japanese population, and the prevalence of AF is expected to continue to rise in Japan, affecting an estimated 10 million people by 2030. 1 AF is a strong risk factor for stroke and death. Randomized clinical trials (RCTs) have shown the benefit of direct oral anticoagulant (DOAC) therapy in reducing the risk of stroke and Editorial p 707

BackgroundLarge-scale investigations on the use of oral anticoagulants including direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) have not included Japanese patients.MethodsWe established the multicenter SAKURA AF Registry to support prospective observational research on the status of anticoagulation treatment, especially with DOAC, for AF in Japan. We enrolled 3266 AF patients treated with warfarin (n=1577) or any of 4 DOACs (n=1689) from 63 institutions (2 cardiovascular centers, 13 affiliated hospitals or community hospitals, and 48 private clinics) in the Tokyo area.ResultsWe conducted our first analysis of the registry data, and although we found equivalent mean age between the DOAC and warfarin users (71.8±9.5 vs. 72.3±9.4 years, p=0.2117), we found a slightly lower risk of stroke (CHADS2 score of 0 or 1 [46.9% vs. 39.4%, p<0.0001]) and significantly better creatinine clearance in DOAC users (70.4±27 vs. 65.6±25.7 mL/min, p<0.0001). Importantly, we documented under-dosing in 32% of warfarin users and inappropriate-low-dosing in 19.7–27.6% of DOAC users.ConclusionsOur initial analysis of the SAKURA AF Registry data clarified the real-world use of anticoagulants, which includes DOACs and warfarin in Japan. The DOAC users were at a lower risk for stroke than the warfarin users. In 20–30% of DOAC users, the dose was inappropriately reduced.

We present a new type of the Hamiltonian replica-exchange method, where the van der Waals radius parameter and not the temperature is exchanged. By decreasing the van der Waals radii, which control spatial sizes of atoms, this Hamiltonian replica-exchange method overcomes the steric restrictions and energy barriers. Furthermore, the simulation based on this method escapes from the local-minimum free-energy states and realizes effective sampling in the conformational space. We applied this method to an alanine dipeptide in aqueous solution and showed the effectiveness of the method by comparing the results with those obtained from the conventional canonical and replica-exchange methods.