GENESIS(Generalized‐Ensemble Simulation System) is a new software package for molecular dynamics (MD) simulations of macromolecules. It has twoMDsimulators, calledATDYNandSPDYN.ATDYNis parallelized based on an atomic decomposition algorithm for the simulations of all‐atom force‐field models as well as coarse‐grained Go‐like models.SPDYNis highly parallelized based on a domain decomposition scheme, allowing large‐scaleMDsimulations on supercomputers. Hybrid schemes combiningOpenMPandMPIare used in both simulators to target modern multicore computer architectures. Key advantages ofGENESISare (1) the highly parallel performance ofSPDYNfor very large biological systems consisting of more than one million atoms and (2) the availability of variousREMDalgorithms (T‐REMD,REUS, multi‐dimensionalREMDfor both all‐atom and Go‐like models under theNVT,NPT,NPAT, andNPγTensembles). The former is achieved by a combination of the midpoint cell method and the efficient three‐dimensional Fast Fourier Transform algorithm, where the domain decomposition space is shared in real‐space and reciprocal‐space calculations. Other features inSPDYN, such as avoiding concurrent memory access, reducing communication times, and usage of parallel input/output files, also contribute to the performance. We show theREMDsimulation results of a mixed (POPC/DMPC) lipid bilayer as a real application usingGENESIS.GENESISis released as free software under theGPLv2licence and can be easily modified for the development of new algorithms and molecular models.WIREs Comput Mol Sci2015, 5:310–323. doi: 10.1002/wcms.1220This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Computer and Information Science > Computer Algorithms and Programming Molecular and Statistical Mechanics > Molecular Dynamics and Monte-Carlo Methods

GENeralized‐Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly parallelized schemes and enhanced conformational sampling algorithms. In this new version, GENESIS 1.1, new functions and advanced algorithms have been added. The all‐atom and coarse‐grained potential energy functions used in AMBER and GROMACS packages now become available in addition to CHARMM energy functions. The performance of MD simulations has been greatly improved by further optimization, multiple time‐step integration, and hybrid (CPU + GPU) computing. The string method and replica‐exchange umbrella sampling with flexible collective variable choice are used for finding the minimum free‐energy pathway and obtaining free‐energy profiles for conformational changes of a macromolecule. These new features increase the usefulness and power of GENESIS for modeling and simulation in biological research.

Large-scale conformational changes in proteins involve barrier-crossing transitions on the complex free energy surfaces of high-dimensional space. Such rare events cannot be efficiently captured by conventional molecular dynamics simulations. Here we show that, by combining the on-the-fly string method and the multi-state Bennett acceptance ratio (MBAR) method, the free energy profile of a conformational transition pathway in Escherichia coli adenylate kinase can be characterized in a high-dimensional space. The minimum free energy paths of the conformational transitions in adenylate kinase were explored by the on-the-fly string method in 20-dimensional space spanned by the 20 largest-amplitude principal modes, and the free energy and various kinds of average physical quantities along the pathways were successfully evaluated by the MBAR method. The influence of ligand binding on the pathways was characterized in terms of rigid-body motions of the lid-shaped ATP-binding domain (LID) and the AMP-binding (AMPbd) domains. It was found that the LID domain was able to partially close without the ligand, while the closure of the AMPbd domain required the ligand binding. The transition state ensemble of the ligand bound form was identified as those structures characterized by highly specific binding of the ligand to the AMPbd domain, and was validated by unrestrained MD simulations. It was also found that complete closure of the LID domain required the dehydration of solvents around the P-loop. These findings suggest that the interplay of the two different types of domain motion is an essential feature in the conformational transition of the enzyme. Conformational transitions of proteins have been postulated to play a central role in various protein functions such as catalysis, allosteric regulation, and signal transduction. Among these, the relation between enzymatic catalysis and dynamics has been particularly well-studied. The target molecule in this study, adenylate kinase from Escherichia coli, exists in an open state which allows binding of its substrates (ATP and AMP), and a closed state in which catalytic reaction occurs. In this molecular simulation study, we have elucidated the atomic details of the conformational transition between the open and the closed states. A combined use of the path search method and the free energy calculation method enabled the transition pathways to be traced in atomic detail on micro- to millisecond time scales. Our simulations revealed that two ligand molecules, AMP and ATP, play a distinctive role in the transition scenario. The specific binding of AMP into the hinge region occurs first and creates a bottleneck in the transition. ATP-binding, which requires the dehydration of an occluded water molecule, is completed at a later stage of the transition.

GENeralized-Ensemble SImulation System (GENESIS) is a molecular dynamics (MD) software developed to simulate the conformational dynamics of a single biomolecule, as well as molecular interactions in large biomolecular assemblies and between multiple biomolecules in cellular environments. To achieve the latter purpose, the earlier versions of GENESIS emphasized high performance in atomistic MD simulations on massively parallel supercomputers, with or without graphics processing units (GPUs). Here, we implemented multiscale MD simulations that include atomistic, coarse-grained, and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations. They demonstrate high performance and are integrated with enhanced conformational sampling algorithms and free-energy calculations without using external programs except for the QM programs. In this article, we review new functions, molecular models, and other essential features in GENESIS version 2.1 and discuss ongoing developments for future releases.

A scheme to approximate the multidimensional potential energy landscape in terms of a minimal number of degrees of freedom is proposed using a linear transformation of the original atomic Cartesian coordinates. For one particular off-lattice model protein the inherent frustration can only be reproduced satisfactorily when a relatively large number of coordinates are employed. However, when this frustration is removed in a Gō-type model, the number of coordinates required is significantly lower, especially around the global potential energy minimum. To aid our interpretation of the results we consider modified disconnectivity graphs where a measure of the structural diversity and a metric relation between the stationary points are incorporated.

The multidrug transporter AcrB transports a broad range of drugs out of the cell by means of the proton-motive force. The asymmetric crystal structure of trimeric AcrB suggests a functionally rotating mechanism for drug transport. Despite various supportive forms of evidence from biochemical and simulation studies for this mechanism, the link between the functional rotation and proton translocation across the membrane remains elusive. Here, calculating the minimum free energy pathway of the functional rotation for the complete AcrB trimer, we describe the structural and energetic basis behind the coupling between the functional rotation and the proton translocation at atomic resolution. Free energy calculations show that protonation of Asp408 in the transmembrane portion of the drug-bound protomer drives the functional rotation. The conformational pathway identifies vertical shear motions among several transmembrane helices, which regulate alternate access of water in the transmembrane as well as peristaltic motions that pump drugs in the periplasm.