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We propose an efficient method to enhance sampling in computer simulations by combining the simulated tempering algorithm with a fast on-the-fly weight determination scheme. The weights are self-updated via a trapezoid rule during the simulated tempering simulation. With our proposed scheme, simulated tempering requires neither prior trial simulations nor complicated update schemes. The advantage of our method over replica exchange molecular dynamics has been demonstrated with the study of the folding of the 20-residue alanine peptide and the aggregation of a trimer formed by the Alzheimer's peptide fragment Aβ16-22. [ABSTRACT FROM AUTHOR]

Many commonly used force fields for protein systems such as AMBER, CHARMM, GROMACS, OPLS, and ECEPP have amino-acid-independent force-field parameters for main-chain torsion-energy terms. Here, we propose a new type of amino-acid-dependent torsion-energy terms in the force fields. As an example, we applied this approach to AMBER ff03 force field and determined new amino-acid-dependent parameters for ψ (N-Cα-C-N) and ζ (Cβ-Cα-C-N) angles for each amino acid by using our optimization method, which is one of the knowledge-based approach. In order to test the validity of the new force-field parameters, we then performed folding simulations of α-helical and β-hairpin peptides, using the optimized force field. The results showed that the new force-field parameters gave structures more consistent with the experimental implications than the original AMBER ff03 force field. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gramicidin A is a linear hydrophobic 15-residue peptide which consists of alternating D- and L-amino acids and forms a unique tertiary structure, called the β6.3-helix, to act as a cation-selective ion channel in the natural conditions. In order to investigate the intrinsic ability of the gramicidin A monomer to form secondary structures, we performed the folding simulation of gramicidin A using a simulated annealing molecular dynamics (MD) method in vacuum mimicking the low-dielectric, homogeneous membrane environment. The initial conformation was a fully extended one. From the 200 different MD runs, we obtained a right-handed β4.4-helix as the lowest-potential-energy structure, and left-handed β4.4-helix, right-handed and left-handed β6.3-helix as local-minimum energy states. These results are in accord with those of the experiments of gramicidin A in homogeneous organic solvent. Our simulations showed a slight right-hand sense in the lower-energy conformations and a quite β-sheet-forming tendency throughout almost the entire sequence. In order to examine the stability of the obtained right-handed β6.3-helix and β4.4-helix structures in more realistic membrane environment, we have also performed all-atom MD simulations in explicit water, ion, and lipid molecules, starting from these β-helix structures. The results suggested that β6.3-helix is more stable than β4.4-helix in the inhomogeneous, explicit membrane environment, where the pore water and the hydrogen bonds between Trp side-chains and lipid-head groups have a role to further stabilize the β6.3-helix conformation. [ABSTRACT FROM AUTHOR]

We give general formulations of the multidimensional multicanonical algorithm, simulated tempering, and replica-exchange method. We generalize the original potential energy function E0 by adding any physical quantity V of interest as a new energy term. These multidimensional generalized-ensemble algorithms then perform a random walk not only in E0 space but also in V space. Among the three algorithms, the replica-exchange method is the easiest to perform because the weight factor is just a product of regular Boltzmann-like factors, while the weight factors for the multicanonical algorithm and simulated tempering are not a priori known. We give a simple procedure for obtaining the weight factors for these two latter algorithms, which uses a short replica-exchange simulation and the multiple-histogram reweighting techniques. As an example of applications of these algorithms, we have performed a two-dimensional replica-exchange simulation and a two-dimensional simulated-tempering simulation using an α-helical peptide system. From these simulations, we study the helix-coil transitions of the peptide in gas phase and in aqueous solution. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The multioverlap molecular dynamics method gives a flat probability distribution in the multidimensional dihedral-angle-distance space, where the dihedral-angle distance of a configuration with respect to a reference state gives a measure for structural similarity. Hence, this method realizes a random walk among specific configurations in the multidimensional dihedral-angle-distance space at a constant temperature and explores widely in the configurational space. We applied the multioverlap molecular dynamics method to a pentapeptide, Met-enkephalin, in gas phase as a test system. Comparing the results of this method with those of the conventional canonical and multicanonical algorithms, we demonstrate its effectiveness. Furthermore, from the detailed free-energy landscape obtained from the results of the multioverlap molecular dynamics simulation, we obtain the transition state between two specific reference configurations of Met-enkephalin. We also deduce the transition pathway between the two specific reference configurations. [ABSTRACT FROM AUTHOR]

In this paper we consider combinations of two well-known generalized-ensemble algorithms, namely, simulated tempering and replica-exchange method. We discuss two examples of such combinations. One is the replica-exchange simulated tempering and the other is the simulated tempering replica-exchange method. In the former method, a short replica-exchange simulation is first performed and the simulated tempering weight factor is obtained by the multiple-histogram reweighting techniques. This process of simulated tempering weight factor determination is faster and simpler than that in the usual iterative process. A long simulated tempering production run is then performed with this weight factor. The latter method is a further extension of the former in which a simulated tempering replica-exchange simulation is performed with a small number of replicas. These algorithms are particularly useful for studying frustrated systems with rough energy landscape. We give the formulations of these two methods in detail and demonstrate their effectiveness taking the example of the system of a 17-residue helical peptide. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We test our prediction method of membrane protein structures with glycophorin A transmembrane dimer and analyze the predicted structures in detail. Our method consists of two parts. In the first part, we obtain the amino-acid sequences of the transmembrane helix regions from one of existing WWW servers and use them as an input for the second part of our method. In the second part, we perform a replica-exchange Monte Carlo simulation of these transmembrane helices with some constraints that indirectly represent surrounding lipid and water effects and identify the predicted structure as the global-minimum-energy state. The structure obtained in the case for the dielectric constant ε = 1.0 is very close to that from the nuclear magnetic resonance experiments, while that for ε = 4.0 is more packed than the native one. Our results imply that the helix­helix interaction is the main driving force for the native structure formation and that the stability of the native structure is determined by the balance of the electrostatic term, van der Waals term, and torsion term, and the contribution of electrostatic energy is indeed important for correct predictions. The inclusion of atomistic details of side chains is essential for estimating this balance accurately because helices are tightly packed. [ABSTRACT FROM AUTHOR]

The replica-exchange multicanonical algorithm and the multicanonical replica-exchange method for molecular dynamics simulations have recently been developed. In the former method the multicanonical weight factor is determined from a short replica-exchange simulation with the multiple-histogram reweighting techniques. A long multicanonical production run with high statistics is then performed with this weight factor. In this method, the process of determining the multicanonical weight factor is faster and simpler than that in the usual iterative determination. The multicanonical replica-exchange method is a further extension of the first in which a replica-exchange multicanonical simulation is performed with a small number of replicas. In this paper, we give the formulations of these two methods for Monte Carlo simulations and demonstrate the effectiveness of these algorithms for a penta peptide in the gas phase. [ABSTRACT FROM AUTHOR]

In Paper I of this series the formulations of the replica-exchange multicanonical algorithm and the multicanonical replica-exchange method for Monte Carlo versions have been presented. The effectiveness of these algorithms were then tested with the system of a penta peptide, Met-enkephalin, in the gas phase. In this article the detailed comparisons of performances of these algorithms together with the regular replica-exchange method are made, taking a more complex system of a 17-residue helical peptide. It is shown that these two new algorithms are more efficient than the regular replica-exchange method. [ABSTRACT FROM AUTHOR]