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GENESIS 2.1: High-Performance Molecular Dynamics Software for Enhanced Sampling and Free-Energy Calculations for Atomistic, Coarse-Grained, and Quantum Mechanics/Molecular Mechanics Models
Jaewoon Jung, Kiyoshi Yagi, Cheng Tan, Hiraku Oshima, Takaharu Mori, Isseki Yu, Yasuhiro Matsunaga, Chigusa Kobayashi, Shingo Ito, Diego Ugarte La Torre, Yuji Sugita
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.
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GENESIS CGDYN: large-scale coarse-grained MD simulation with dynamic load balancing for heterogeneous biomolecular systems
Jaewoon Jung, Cheng Tan, Sugita
Residue-level coarse-grained (CG) molecular dynamics (MD) simulation is widely used to investigate slow biological processes that involve multiple proteins, nucleic acids, and their complexes. Biomolecules in a large simulation system are distributed non-uniformly, limiting computational efficiency with conventional methods. Here, we develop a hierarchical domain decomposition scheme with dynamic load balancing for heterogeneous biomolecular systems to keep computational efficiency even after drastic changes in particle distribution. These schemes are applied to the dynamics of intrinsically disordered protein (IDP) droplets. During the fusion of two droplets, we find that the changes in droplet shape correlate with the mixing of IDP chains. Additionally, we simulate large systems with multiple IDP droplets, achieving simulation sizes comparable to those observed in microscopy. In our MD simulations, we directly observe Ostwald ripening, a phenomenon where small droplets dissolve and their molecules redeposit into larger droplets. These methods have been implemented in CGDYN of the GENESIS software, offering a tool for investigating mesoscopic biological processes using the residue-level CG models.
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Micelle-like clusters in phase-separated Nanog condensates: A molecular simulation study
Azuki Mizutani, Cheng Tan, Yuji Sugita, Shoji Takada
The phase separation model for transcription suggests that transcription factors (TFs), coactivators, and RNA polymerases form biomolecular condensates around active gene loci and regulate transcription. However, the structural details of condensates remain elusive. In this study, for Nanog, a master TF in mammalian embryonic stem cells known to form protein condensates in vitro, we examined protein structures in the condensates using residue-level coarse-grained molecular simulations. Human Nanog formed micelle-like clusters in the condensate. In the micelle-like cluster, the C-terminal disordered domains, including the tryptophan repeat (WR) regions, interacted with each other near the cluster center primarily via hydrophobic interaction. In contrast, hydrophilic disordered N-terminal and DNA-binding domains were exposed on the surface of the clusters. Electrostatic attractions of these surface residues were responsible for bridging multiple micelle-like structures in the condensate. The micelle-like structure and condensate were dynamic and liquid-like. Mutation of tryptophan residues in the WR region which was implicated to be important for a Nanog function resulted in dissolution of the Nanog condensate. Finally, to examine the impact of Nanog cluster to DNA, we added DNA fragments to the Nanog condensate. Nanog DNA-binding domains exposed to the surface of the micelle-like cluster could recruit more than one DNA fragments, making DNA-DNA distance shorter.
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Extension of the iSoLF implicit-solvent coarse-grainedmodel for multicomponent lipid bilayers
Diego Ugarte La Torre, Shoji Takada, Yuji Sugita
iSoLF is a coarse-grained (CG) model for lipid molecules with the implicit-solvent approximation used in molecular dynamics (MD) simulations of biological membranes. Using the original iSoLF (iSoLFv1), MD simulations of lipid bilayers consisting of either POPC or DPPC and these bilayers, including membrane proteins, can be performed. Here, we improve the original model, explicitly treating the electrostatic interactions between different lipid molecules and adding CG particle types. As a result, the available lipid types increase to 30. To parameterize the potential functions of the new model, we performed all-atom MD simulations of each lipid at three different temperatures using the CHARMM36 force field and the modified TIP3P model. Then, we parameterized both the bonded and non-bonded interactions to fit the area per lipid and the membrane thickness of each lipid bilayer by using the multistate Boltzmann Inversion method. The final model reproduces the area per lipid and the membrane thickness of each lipid bilayer at the three temperatures. We also examined the applicability of the new model, iSoLFv2, to simulate the phase behaviors of mixtures of DOPC and DPPC at different concentrations. The simulation results with iSoLFv2 are consistent with those using Dry Martini and Martini 3, although iSoLFv2 requires much fewer computations. iSoLFv2 has been implemented in the GENESIS MD software and is publicly available.
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Acceleration of generalized replica exchange with solute tempering simulations of large biological systems on massively parallel supercomputer
Jaewoon Jung, Chigusa Kobayashi, Yuji Sugita
Generalized replica exchange with solute tempering (gREST) is one of the enhanced sampling algorithms for proteins or other systems with rugged energy landscapes. Unlike the replica-exchange molecular dynamics (REMD) method, solvent temperatures are the same in all replicas, while solute temperatures are different and are exchanged frequently between replicas for exploring various solute structures. Here, we apply the gREST scheme to large biological systems containing over one million atoms using a large number of processors in a supercomputer. First, communication time on a multi-dimensional torus network is reduced by matching each replica to MPI processors optimally. This is applicable not only to gREST but also to other multi-copy algorithms. Second, energy evaluations, which are necessary for the multistate bennet acceptance ratio (MBAR) method for free energy estimations, are performed on-the-fly during the gREST simulations. Using these two advanced schemes, we observed 57.72 ns/day performance in 128-replica gREST calculations with 1.5 million atoms system using 16,384 nodes in Fugaku. These schemes implemented in the latest version of GENESIS software could open new possibilities to answer unresolved questions on large biomolecular complex systems with slow conformational dynamics.
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Highly Charged Proteins and Their Repulsive Interactions Antagonize Biomolecular Condensation
Cheng Tan, Ai Niitsu, Yuji Sugita
Biomolecular condensation is involved in various cellular processes; therefore, regulation of condensation is crucial to prevent deleterious protein aggregation and maintain a stable cellular environment. Recently, a class of highly charged proteins, known as heat-resistant obscure (Hero) proteins, was shown to protect other client proteins from pathological aggregation. However, the molecular mechanisms by which Hero proteins protect other proteins from aggregation remain unknown. In this study, we performed multiscale molecular dynamics (MD) simulations of Hero11, a Hero protein, and the C-terminal low-complexity domain (LCD) of the transactive response DNA-binding protein 43 (TDP-43), a client protein of Hero11, under various conditions to examine their interactions with each other. We found that Hero11 permeates into the condensate formed by the LCD of TDP-43 (TDP-43-LCD) and induces changes in conformation, intermolecular interactions, and dynamics of TDP-43-LCD. We also examined possible Hero11 structures in atomistic and coarse-grained MD simulations and found that Hero11 with a higher fraction of disordered region tends to assemble on the surface of the condensates. Based on the simulation results, we have proposed three possible mechanisms for Hero11’s regulatory function: (i) In the dense phase, TDP-43-LCD reduces contact with each other and shows faster diffusion and decondensation due to the repulsive Hero11–Hero11 interactions. (ii) In the dilute phase, the saturation concentration of TDP-43-LCD is increased, and its conformation is relatively more extended and variant, induced by the attractive Hero11–TDP-43-LCD interactions. (iii) Hero11 on the surface of small TDP-43-LCD condensates can contribute to avoiding their fusion due to repulsive interactions. The proposed mechanisms provide new insights into the regulation of biomolecular condensation in cells under various conditions.
