Short Molecular Dynamics Research Articles

TOLEDO: enhancing Maestro GUI for non-expert users to perform massive MD simulations

Classical Molecular Dynamics (MD) simulates the dynamical evolution of biological systems at the atomic level. Using MD in conjunction with high-performance computing (HPC) architectures, we can evaluate the possible interactions between a ligand library against one protein target to find a drug that can influence a protein target to cure a disease. Simultaneously, we can also obtain information about their dynamic evolution. One of the primary software packages for MD simulations is Desmond, which employs Maestro for the setup, execution, and analysis of MD through a graphical user interface (GUI), which is suitable even for non-expert users. However, using the GUI, users can typically run only one short (less than 1000 ns) MD each time. Our work aims to create a method/protocol to run several MD simulations simultaneously on a remote HPC cluster within Maestro-Desmond. In this work, we provide TOLEDO (Throughput Optimization of Ligand-Protein Systems Exploration through Dynamics simulation in Optimized HPC systems) to overcome such limitations and run several MD simulations simultaneously. The best feature of TOLEDO is its independence from the usual time constraints of many clusters, with storage space being the only limitation. To run TOLEDO, we prepare/set up the protein-ligand complex before running MD via Maestro GUI. Next, we run the main TOLEDO script for several MD simulations on a supercomputer. When TOLEDO finishes, users obtain reports and graphics. The obtained results are easily interpretable. In essence, TOLEDO significantly enhances MD throughput beyond the capabilities of the Maestro GUI.

Exploring Conformational Landscapes Along Anharmonic Low-Frequency Vibrations.

We aim to automatize the identification of collective variables to simplify and speed up enhanced sampling simulations of conformational dynamics in biomolecules. We focus on anharmonic low-frequency vibrations that exhibit fluctuations on time scales faster than conformational transitions but describe a path of least resistance toward structural change. A key challenge is that harmonic approximations are ill-suited to characterize these vibrations, which are observed at far-infrared frequencies and are easily excited by thermal collisions at room temperature. Here, we approached this problem with a frequency-selective anharmonic (FRESEAN) mode analysis that does not rely on harmonic approximations and successfully isolates anharmonic low-frequency vibrations from short molecular dynamics simulation trajectories. We applied FRESEAN mode analysis to simulations of alanine dipeptide, a common test system for enhanced sampling simulation protocols, and compared the performance of isolated low-frequency vibrations to conventional user-defined collective variables (here backbone dihedral angles) in enhanced sampling simulations. The comparison shows that enhanced sampling along anharmonic low-frequency vibrations not only reproduces known conformational dynamics but can even further improve the sampling of slow transitions compared to user-defined collective variables. Notably, free energy surfaces spanned by low-frequency anharmonic vibrational modes exhibit lower barriers associated with conformational transitions relative to representations in backbone dihedral space. We thus conclude that anharmonic low-frequency vibrations provide a promising path for highly effective and fully automated enhanced sampling simulations of conformational dynamics in biomolecules.

Seebeck Coefficient of Ionic Conductors from Bayesian Regression Analysis.

We propose a novel approach to evaluating the ionic Seebeck coefficient in electrolytes from relatively short equilibrium molecular dynamics simulations, based on the Green-Kubo theory of linear response and Bayesian regression analysis. By exploiting the probability distribution of the off-diagonal elements of a Wishart matrix, we develop a consistent and unbiased estimator for the Seebeck coefficient, whose statistical uncertainty can be arbitrarily reduced in the long-time limit. We assess the efficacy of our method by benchmarking it against extensive equilibrium molecular dynamics simulations conducted on molten CsF using empirical force fields. We then employ this procedure to calculate the Seebeck coefficient of molten NaCl, KCl, and LiCl using neural network force fields trained on ab initio data over a range of pressure-temperature conditions.

Exploring Biomolecular Conformational Dynamics with Polarizable Force Field AMOEBA and Enhanced Sampling Method Milestoning.

Conformational dynamics play a crucial role in determining the behavior of the biomolecules. Polarizable force fields, such as AMOEBA, can accurately capture electrostatic interactions underlying the conformational space. However, applying a polarizable force field in molecular dynamics (MD) simulations can be computationally expensive, especially in studying long-time-scale dynamics. To overcome this challenge, we incorporated the AMOEBA potential with Milestoning, an enhanced sampling method in this work. This integration allows us to efficiently sample the rare and important conformational states of a biomolecule by using many short and independent molecular dynamics trajectories with the AMOEBA force field. We applied this method to investigate the conformational dynamics of alanine dipeptide, DNA, and RNA A-B form conversion. Well-converged thermodynamic and kinetic properties were obtained, including the free energy difference, mean first passage time, and critical transitions between states. Our results demonstrate the power of integrating polarizable force fields with enhanced sampling methods in quantifying the thermodynamic and kinetic properties of biomolecules at the atomic level.

Extracting binding energies and binding modes from biomolecular simulations of fragment binding to endothiapepsin.

Fragment-based drug discovery (FBDD) aims to discover a set of small binding fragments that may be subsequently linked together. Therefore, in-depth knowledge of the individual fragments' structural and energetic binding properties is essential. In addition to experimental techniques, the direct simulation of fragment binding by molecular dynamics (MD) simulations became popular to characterize fragment binding. However, former studies showed that long simulation times and high computational demands per fragment are needed, which limits applicability in FBDD. Here, we performed short, unbiased MD simulations of direct fragment binding to endothiapepsin, a well-characterized model system of pepsin-like aspartic proteases. To evaluate the strengths and limitations of short MD simulations for the structural and energetic characterization of fragment binding, we predicted the fragments' absolute free energies and binding poses based on the direct simulations of fragment binding and compared the predictions to experimental data. The predicted absolute free energies are in fair agreement with the experiment. Combining the MD data with binding mode predictions from molecular docking approaches helped to correctly identify the most promising fragments for further chemical optimization. Importantly, all computations and predictions were done within 5 days, suggesting that MD simulations may become a viable tool in FBDD projects.

PigmentHunter: A point-and-click application for automated chlorophyll-protein simulations.

Chlorophyll proteins (CPs) are the workhorses of biological photosynthesis, working together to absorb solar energy, transfer it to chemically active reaction centers, and control the charge-separation process that drives its storage as chemical energy. Yet predicting CP optical and electronic properties remains a serious challenge, driven by the computational difficulty of treating large, electronically coupled molecular pigments embedded in a dynamically structured protein environment. To address this challenge, we introduce here an analysis tool called PigmentHunter, which automates the process of preparing CP structures for molecular dynamics (MD), running short MD simulations on the nanoHUB.org science gateway, and then using electrostatic and steric analysis routines to predict optical absorption, fluorescence, and circular dichroism spectra within a Frenkel exciton model. Inter-pigment couplings are evaluated using point-dipole or transition-charge coupling models, while site energies can be estimated using both electrostatic and ring-deformation approaches. The package is built in a Jupyter Notebook environment, with a point-and-click interface that can be used either to manually prepare individual structures or to batch-process many structures at once. We illustrate PigmentHunter's capabilities with example simulations on spectral line shapes in the light harvesting 2 complex, site energies in the Fenna-Matthews-Olson protein, and ring deformation in photosystems I and II.

Using machine learning with atomistic surface and local water features to predict heterogeneous ice nucleation.

Heterogeneous ice nucleation (HIN) has applications in climate science, nanotechnology, and cryopreservation. Ice nucleation on the earth's surface or in the atmosphere usually occurs heterogeneously involving foreign substrates, known as ice nucleating particles (INPs). Experiments identify good INPs but lack sufficient microscopic resolution to answer the basic question: What makes a good INP? We employ molecular dynamics (MD) simulations in combination with machine learning (ML) to address this question. Often, the large amount of computational cost required to cross the nucleation barrier and observe HIN in MD simulations is a practical limitation. We use information obtained from short MD simulations of atomistic surface and water models to predict the likelihood of HIN. We consider 153 atomistic substrates with some surfaces differing in elemental composition and others only in terms of lattice parameters, surface morphology, or surface charges. A range of water features near the surface (local) are extracted from short MD simulations over a time interval (≤300 ns) where ice nucleation has not initiated. Three ML classification models, Random Forest (RF), support vector machine, and Gaussian process classification are considered, and the accuracies achieved by all three approaches lie within their statistical uncertainties. Including local water features is essential for accurate prediction. The accuracy of our best RF classification model obtained including both surface and local water features is 0.89 ± 0.05. A similar accuracy can be achieved including only local water features, suggesting that the important surface properties are largely captured by the local water features. Some important features identified by ML analysis are local icelike structures, water density and polarization profiles perpendicular to the surface, and the two-dimensional lattice match to ice. We expect that this work, with its strong focus on realistic surface models, will serve as a guide to the identification or design of substrates that can promote or discourage ice nucleation.

Molecular dynamics simulations as a guide for modulating small molecule aggregation

Small colloidally aggregating molecules (SCAMs) can be problematic for biological assays in drug discovery campaigns. However, the self-associating properties of SCAMs have potential applications in drug delivery and analytical biochemistry. Consequently, the ability to predict the aggregation propensity of a small organic molecule is of considerable interest. Chemoinformatics-based filters such as ChemAGG and Aggregator Advisor offer rapid assessment but are limited by the assay quality and structural diversity of their training set data. Complementary to these tools, we explore here the ability of molecular dynamics (MD) simulations as a physics-based method capable of predicting the aggregation propensity of diverse chemical structures. For a set of 32 molecules, using simulations of 100 ns in explicit solvent, we find a success rate of 97% (one molecule misclassified) as opposed to 75% by Aggregator Advisor and 72% by ChemAGG. These short timescale MD simulations are representative of longer microsecond trajectories and yield an informative spectrum of aggregation propensities across the set of solutes, capturing the dynamic behaviour of weakly aggregating compounds. Implicit solvent simulations using the generalized Born model were less successful in predicting aggregation propensity. MD simulations were also performed to explore structure-aggregation relationships for selected molecules, identifying chemical modifications that reversed the predicted behaviour of a given aggregator/non-aggregator compound. While lower throughput than rapid cheminformatics-based SCAM filters, MD-based prediction of aggregation has potential to be deployed on the scale of focused subsets of moderate size, and, depending on the target application, provide guidance on removing or optimizing a compound’s aggregation propensity.Graphical

More with less: Harvesting transition mechanism, free energy, and rates from short parallel molecular dynamics simulations

More with less: Harvesting transition mechanism, free energy, and rates from short parallel molecular dynamics simulations

Assessing the performance of MM/PBSA and MM/GBSA methods. 10. Prediction reliability of binding affinities and binding poses for RNA-ligand complexes.

Ribonucleic acid (RNA)-ligand interactions play a pivotal role in a wide spectrum of biological processes, ranging from protein biosynthesis to cellular reproduction. This recognition has prompted the broader acceptance of RNA as a viable candidate for drug targets. Delving into the atomic-scale understanding of RNA-ligand interactions holds paramount importance in unraveling intricate molecular mechanisms and further contributing to RNA-based drug discovery. Computational approaches, particularly molecular docking, offer an efficient way of predicting the interactions between RNA and small molecules. However, the accuracy and reliability of these predictions heavily depend on the performance of scoring functions (SFs). In contrast to the majority of SFs used in RNA-ligand docking, the end-point binding free energy calculation methods, such as molecular mechanics/generalized Born surface area (MM/GBSA) and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA), stand as theoretically more rigorous approaches. Yet, the evaluation of their effectiveness in predicting both binding affinities and binding poses within RNA-ligand systems remains unexplored. This study first reported the performance of MM/PBSA and MM/GBSA with diverse solvation models, interior dielectric constants (εin) and force fields in the context of binding affinity prediction for 29 RNA-ligand complexes. MM/GBSA is based on short (5 ns) molecular dynamics (MD) simulations in an explicit solvent with the YIL force field; the GBGBn2 model with higher interior dielectric constant (εin = 12, 16 or 20) yields the best correlation (Rp = -0.513), which outperforms the best correlation (Rp = -0.317, rDock) offered by various docking programs. Then, the efficacy of MM/GBSA in identifying the near-native binding poses from the decoys was assessed based on 56 RNA-ligand complexes. However, it is evident that MM/GBSA has limitations in accurately predicting binding poses for RNA-ligand systems, particularly compared with notably proficient docking programs like rDock and PLANTS. The best top-1 success rate achieved by MM/GBSA rescoring is 39.3%, which falls below the best results given by docking programs (50%, PLNATS). This study represents the first evaluation of MM/PBSA and MM/GBSA for RNA-ligand systems and is expected to provide valuable insights into their successful application to RNA targets.

Data-driven molecular dynamics simulation of water isotope separation using a catalytically active ultrathin membrane.

Water isotope separation, specifically separating heavy from light water, is a technologically important problem due to the usage of heavy water in applications such as nuclear magnetic resonance, nuclear power, and spectroscopy. Separation of heavy water from light water is difficult due to very similar physical and chemical properties between the isotopes. We show that a catalytically active ultrathin membrane (e.g., a nanopore in MoS2) can enable chemical exchange processes and physicochemical mechanisms that lead to efficient separation of deuterium from hydrogen. The separation process is inherently multiscale in nature with the shorter times representing chemical exchange processes and the longer timescales representing the transport phenomena. To bridge the timescales, we employ a deep learning methodology which uses short time scale ab initio molecular dynamics data for training and extends the timescales to the classical molecular dynamics regime to demonstrate isotope separation and reveal the underlying complex physicochemical processes.

Dealing with Induced Fit, Conformational Selection, and Secondary Poses in Molecular Dynamics Simulations for Reliable Free Energy Predictions.

In this study, we have tested the performance of standard molecular dynamics (MD) simulations, replicates of shorter standard MD simulations, and Hamiltonian Replica Exchange (HREM) simulations for the sampling of two macrocyclic hosts for guest delivery, characterized by induced fit (phenyl-based host) and conformation selection (naphthyl-based host) and of the ODR-BRD4(I) drug-receptor system where the ligand can assume two main poses. For the optimization of the HREM simulation, we have proposed and tested an on-the-fly iterative scheme for equalizing the acceptance ratio along the replica progression at a constant replica number resulting in a moderate impact of the sampling efficiency. Concerning standard MD, we have found that, while splitting the total allocated simulation time in short MD replicates can reproduce the sampling efficiency of HREM in the phenyl-based host and in the ODR-BRD4(I) complex, in the naphthyl-based macrocycle, characterized by long-lived metastable states, enhanced sampling techniques are the only viable alternative for a reliable canonical sampling of the rugged conformational landscape.

Understanding Ionic Diffusion Mechanisms in Li2S Coatings for Solid-State Batteries: Development of a Tailored Reactive Force Field for Multiscale Simulations.

In order to investigate Li2S as a potential protective coating for lithium anode batteries using superionic electrolytes, we need to describe reactions and transport for systems at scales of >10,000 atoms for time scales beyond nanoseconds, which is most impractical for quantum mechanics (QM) calculations. To overcome this issue, here, we first report the development of the reactive analytical force field (ReaxFF) based on density functional theory (DFT) calculations on model systems at the PBE0/TZVP and M062X/TZVP levels. Then, we carry out reactive molecular dynamics simulations (RMD) for up to 20 ns to investigate the diffusion mechanisms in bulk Li2S as a function of vacancy density, determining the activation barrier for diffusion and conductivity. We show that RMD predictions for diffusion and conductivity are comparable to experiments, while results on model systems are consistent with and validated by short (10-100 ps) ab initio molecular dynamics (AIMD). This new ReaxFF for Li2S systems enables practical RMD on spatial scales of 10-100 nm (10,000 to 10 million atoms) for the time scales of 20 ns required to investigate predictively the interfaces between electrodes and electrolytes, electrodes and coatings, and coatings and electrolytes during the charging and discharging processes.

Efficient Modeling of Quantum Dynamics of Charge Carriers in Materials Using Short Nonequilibrium Molecular Dynamics.

Nonadiabatic molecular dynamics provides essential insights into excited-state processes, but it is computationally intense and simplifications are needed. The classical path approximation provides critical savings. Still, long heating and equilibration steps are required. We demonstrate that practical results can be obtained with short, partially equilibrated ab initio trajectories. Once the system's structure is adequate and essential fluctuations are sampled, the nonadiabatic Hamiltonian can be constructed. Local structures require only 1-2 ps trajectories, as demonstrated with point defects in metal halide perovskites. Short trajectories represent anharmonic motions common in defective structures, an essential improvement over the harmonic approximation around the optimized geometry. Glassy systems, such as grain boundaries, require different simulation protocols, e.g., involving machine learning force fields. 10-fold shorter trajectories generate 10-20% time scale errors, which are acceptable, given experimental uncertainties and other approximations. The practical NAMD protocol enables fast screening of excited-state dynamics for rapid exploration of new materials.

Critical Assessment of Self-Consistency Checks in the All-Atom Molecular Dynamics Simulation of Intrinsically Disordered Proteins.

All atom simulations can be used to quantify conformational properties of Intrinsically Disordered Proteins (IDP). However, simulations must satisfy convergence checks to ensure observables computed from simulation are reliable and reproducible. While absolute convergence is purely a theoretical concept requiring infinitely long simulation, a more practical, yet rigorous, approach is to impose Self Consistency Checks (SCCs) to gain confidence in the simulated data. Currently there is no study of SCCs in IDPs, unlike their folded counterparts. In this paper, we introduce different criteria for self-consistency checks for IDPs. Next, we impose these SCCs to critically assess the performance of different simulation protocols using the N terminal domain of HIV Integrase and the linker region of SARS-CoV-2 Nucleoprotein as two model IDPs. All simulation protocols begin with all-atom implicit solvent Monte Carlo (MC) simulation and subsequent clustering of MC generated conformations to create the representative structures of the IDPs. These representative structures serve as the initial structure for subsequent molecular dynamics (MD) runs with explicit solvent. We conclude that generating multiple short (∼3 μs) MD simulation trajectories─all starting from the most representative MC generated conformation─and merging them is the protocol of choice due to (i) its ability to satisfy multiple SCCs, (ii) consistently reproducing experimental data, and (iii) the efficiency of running independent trajectories in parallel by harnessing multiple cores available in modern GPU clusters. Running one long trajectory (greater than 20 μs) can also satisfy the first two criteria but is less desirable due to prohibitive computation time. These findings help resolve the challenge of identifying a usable starting configuration, provide an objective measure of SCC, and establish rigorous criteria to determine the minimum length (for one long simulation) or number of trajectories needed in all-atom simulation of IDPs.

Enhancing Conformational Sampling for Intrinsically Disordered and Ordered Proteins by Variational Autoencoder.

Intrinsically disordered proteins (IDPs) account for more than 50% of the human proteome and are closely associated with tumors, cardiovascular diseases, and neurodegeneration, which have no fixed three-dimensional structure under physiological conditions. Due to the characteristic of conformational diversity, conventional experimental methods of structural biology, such as NMR, X-ray diffraction, and CryoEM, are unable to capture conformational ensembles. Molecular dynamics (MD) simulation can sample the dynamic conformations at the atomic level, which has become an effective method for studying the structure and function of IDPs. However, the high computational cost prevents MD simulations from being widely used for IDPs conformational sampling. In recent years, significant progress has been made in artificial intelligence, which makes it possible to solve the conformational reconstruction problem of IDP with fewer computational resources. Here, based on short MD simulations of different IDPs systems, we use variational autoencoders (VAEs) to achieve the generative reconstruction of IDPs structures and include a wider range of sampled conformations from longer simulations. Compared with the generative autoencoder (AEs), VAEs add an inference layer between the encoder and decoder in the latent space, which can cover the conformational landscape of IDPs more comprehensively and achieve the effect of enhanced sampling. Through experimental verification, the Cα RMSD between VAE-generated and MD simulation sampling conformations in the 5 IDPs test systems was significantly lower than that of AE. The Spearman correlation coefficient on the structure was higher than that of AE. VAE can also achieve excellent performance regarding structured proteins. In summary, VAEs can be used to effectively sample protein structures.

Deciphering Selectivity Mechanism of BRD9 and TAF1(2) toward Inhibitors Based on Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations

BRD9 and TAF1(2) have been regarded as significant targets of drug design for clinically treating acute myeloid leukemia, malignancies, and inflammatory diseases. In this study, multiple short molecular dynamics simulations combined with the molecular mechanics generalized Born surface area method were employed to investigate the binding selectivity of three ligands, 67B, 67C, and 69G, to BRD9/TAF1(2) with IC50 values of 230/59 nM, 1400/46 nM, and 160/410 nM, respectively. The computed binding free energies from the MM-GBSA method displayed good correlations with that provided by the experimental data. The results indicate that the enthalpic contributions played a critical factor in the selectivity recognition of inhibitors toward BRD9 and TAF1(2), indicating that 67B and 67C could more favorably bind to TAF1(2) than BRD9, while 69G had better selectivity toward BRD9 over TAF1(2). In addition, the residue-based free energy decomposition approach was adopted to calculate the inhibitor-residue interaction spectrum, and the results determined the gatekeeper (Y106 in BRD9 and Y1589 in TAF1(2)) and lipophilic shelf (G43, F44, and F45 in BRD9 and W1526, P1527, and F1528 in TAF1(2)), which could be identified as hotspots for designing efficient selective inhibitors toward BRD9 and TAF1(2). This work is also expected to provide significant theoretical guidance and insightful molecular mechanisms for the rational designs of efficient selective inhibitors targeting BRD9 and TAF1(2).

Generation of unfolded outer membrane protein ensembles defined by hydrodynamic properties.

Outer membrane proteins (OMPs) must exist as an unfolded ensemble while interacting with a chaperone network in the periplasm of Gram-negative bacteria. Here, we developed a method to model unfolded OMP (uOMP) conformational ensembles using the experimental properties of two well-studied OMPs. The overall sizes and shapes of the unfolded ensembles in the absence of a denaturant were experimentally defined by measuring the sedimentation coefficient as a function of urea concentration. We used these data to model a full range of unfolded conformations by parameterizing a targeted coarse-grained simulation protocol. The ensemble members were further refined by short molecular dynamics simulations to reflect proper torsion angles. The final conformational ensembles have polymer properties different from unfolded soluble and intrinsically disordered proteins and reveal inherent differences in the unfolded states that necessitate further investigation. Building these uOMP ensembles advances the understanding of OMP biogenesis and provides essential information for interpreting structures of uOMP-chaperone complexes.

Relation in ligand dynamics and protein mutation using unsupervised machine learning.

Drug resistance mutation, which decreases ligand binding affinity to the target biomolecule, is a crucial issue all over the world. To overcome this issue, many approaches are proposed and tried. Free energy calculations are an effective and widely used method to estimate the ligand binding affinity. Relative free energy calculations can estimate the influence of the mutation on the ligand binding. However, the accuracy of the estimation should be limited partly because of insufficient sampling and relaxation of the mutants in the short molecular dynamics (MD) simulations. On the other hand, longer MD simulations make the calculation cost incredibly expensive. To improve the accuracy and computational cost, we have performed a machine-learning-assisted analysis of MD simulations [Yasuda, Commun. Biol. (2022)] of mutant protein-ligand systems. We used nilotinib-Abl-kinase systems, which were previously reported by other groups [Hauser, Commun. biol. (2018), Aldeghi, ACS Cent. Sci. (2019) ]. Our approach can compare the difference in the protein dynamics on ligand binding using unsupervised learning and extracts features of the dynamics of each mutant protein. We will show the relation of the feature to the ligand-binding affinity. Furthermore, interpretation of the feature enables us to understand the part of the ligand that shows different dynamics induced by the mutants. This would provide hints for the mechanics of the binding and improvements of the ligand.

DeepWEST: Deep Learning of Kinetic Models with the Weighted Ensemble Simulation Toolkit for Enhanced Sampling.

Recent advances in computational power and algorithms have enabled molecular dynamics (MD) simulations to reach greater time scales. However, for observing conformational transitions associated with biomolecular processes, MD simulations still have limitations. Several enhanced sampling techniques seek to address this challenge, including the weighted ensemble (WE) method, which samples transitions between metastable states using many weighted trajectories to estimate kinetic rate constants. However, initial sampling of the potential energy surface has a significant impact on the performance of WE, i.e., convergence and efficiency. We therefore introduce deep-learned kinetic modeling approaches that extract statistically relevant information from short MD trajectories to provide a well-sampled initial state distribution for WE simulations. This hybrid approach overcomes any statistical bias to the system, as it runs short unbiased MD trajectories and identifies meaningful metastable states of the system. It is shown to provide a more refined free energy landscape closer to the steady state that could efficiently sample kinetic properties such as rate constants.