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At least 37 records · Page 2

Multitask Machine Learning of Collective Variables for Enhanced Sampling of Rare Events

Computing accurate reaction rates is a central challenge in computational chemistry and biology because of the high cost of free energy estimation with unbiased molecular dynamics. In this work, a data-driven machine learning algorithm is devised to learn collective variables with a multitask neural network, where a common upstream part reduces the high dimensionality of atomic configurations to a low dimensional latent space and separate downstream parts map the latent space to predictions of basin class labels and potential energies. Here, the resulting latent space is shown to be an effective low-dimensional representation, capturing the reaction progress and guiding effective umbrella sampling to obtain accurate free energy landscapes. This approach is successfully applied to model systems including a 5D Müller Brown model, a 5D three-well model, the alanine dipeptide in vacuum, and an Au(110) surface reconstruction unit reaction. It enables automated dimensionality reduction for energy controlled reactions in complex systems, offers a unified and data-efficient framework that can be trained with limited data, and outperforms single-task learning approaches, including autoencoders.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Variational control forces for enhanced sampling of nonequilibrium molecular dynamics simulations

We introduce a variational algorithm to estimate the likelihood of a rare event within a nonequilibrium molecular dynamics simulation through the evaluation of an optimal control force. Optimization of a control force within a chosen basis is made possible by explicit forms for the gradients of a cost function in terms of the susceptibility of driven trajectories to changes in variational parameters. We consider probabilities of time-integrated dynamical observables as characterized by their large deviation functions and find that in many cases, the variational estimate is quantitatively accurate. Additionally, we provide expressions to exactly correct the variational estimate that can be evaluated directly. We benchmark this algorithm against the numerically exact solution of a model of a driven particle in a periodic potential, where the control force can be represented with a complete basis. Additionally, we then demonstrate the utility of the algorithm in a model of repulsive particles on a line, which undergo a dynamical phase transition, resulting in singular changes to the form of the optimal control force. In both systems, we find fast convergence and are able to evaluate large deviation functions with significant increases in statistical efficiency over alternative Monte Carlo approaches.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Replication Data for: Multitask Machine Learning of Collective Variables for Enhanced Sampling of Rare Events

The data underlying this published work have been made publicly available in this repository as part of the IMASC Data Management Plan. This work was supported as part of the Integrated Mesoscale Architectures for Sustainable Catalysis (IMASC), an Energy Frontier Research Center funded by the U.S. Department of Energy, Office of Science, Basic Energy Sciences under Award # DE-SC0012573.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19

In this work, we present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

60 APPLIED LIFE SCIENCES↗

Enhanced Configurational Sampling Approaches to Alchemical Ligand Binding Free Energy Simulations: Current Status and Challenges

In this study, ligand binding free energy simulations (LB-FES) have been routine tasks in modern drug discovery campaign. A long-standing challenge for LB-FES is the difficulty in adequately sampling nontrivial environmental reorganizations in response to ligand binding. Therefore, various enhanced configurational sampling (ECS) approaches were devised to speed up fluctuations of relevant slow degrees of freedom (SDOF) and ensure simulation convergence. However, in contrast to the achievements in parametrization, software performance, and workflow automation, efficient ECS methodology suitable for high throughput screening remains in an early stage of development. Here, a review of ECS developments with LB-FES is presented, revisiting current approaches and underlining the major technical pitfalls and challenges. This Perspective focuses on alchemical LB-FES on account of their predominant role in high throughput drug screening as well as the established partnership with ECS. The critical aspects of designing ECS approaches, from both theoretical and applied perspectives, are described. This work is intended to provide a contemporary review of the scientific, technical, and practical issues associated with the accelerating convergence of alchemical LBFES.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Ensemble Simulations and Experimental Free Energy Distributions: Evaluation and Characterization of Isoxazole Amides as SMYD3 Inhibitors

Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein, we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcriptional regulation in cell proliferation, cell cycle, and human carcinogenesis. Experimental measurements using the scintillation proximity assay show that the distributions of binding free energies from a large number of independent measurements exhibit non-normal properties. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to predict the binding free energies and to provide a detailed chemical insight into the nature of ligand-protein binding. Our results show that the 1-trajectory ESMACS protocol works well for the set of ligands studied here. Although one unexplained outlier exists, we obtain excellent statistical ranking across the set of compounds from the ESMACS protocol and good agreement between calculations and experiments for the relative binding free energies from the TIES protocol. ESMACS and TIES are again found to be powerful protocols for the accurate comparison of the binding free energies.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

The performance of ensemble-based free energy protocols in computing binding affinities to ROS1 kinase

Optimization of binding affinities for compounds to their target protein is a primary objective in drug discovery. Herein we report on a collaborative study that evaluates a set of compounds binding to ROS1 kinase. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to rank the binding free energies. The predicted binding free energies from ESMACS simulations show good correlations with experimental data for subsets of the compounds. Consistent binding free energy differences are generated for TIES and ESMACS. Although an unexplained overestimation exists, we obtain excellent statistical rankings across the set of compounds from the TIES protocol, with a Pearson correlation coefficient of 0.90 between calculated and experimental activities.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Custom-trained Machine-learning Interatomic Potentials: ZnCl2 Aqueous Solution

This dataset was generated using an iterative active-learning strategy implemented in the ArcaNN software package (https://github.com/arcann-chem/arcann_training) to train machine-learning interatomic potentials for aqueous ZnCl2 solutions. Each active-learning cycle consisted of three stages: training, exploration, and labeling. The initial training set combined configurations generated in this work from enhanced-sampling ab initio molecular dynamics simulations with configurations from a previously reported neural-network-potential study of aqueous ZnCl2. The enhanced-sampling ab initio molecular dynamics simulations involved Zn–Cl separation and the chloride coordination number around Zn²? as collective variables. These configurations served as the seed dataset. Subsequent active-learning cycles expanded the training set by identifying and labeling configurations that were poorly represented by the current models, thereby improving coverage of ion-association states and changes in local coordination and charge-state environments relevant to the solution free-energy landscape. For all selected configurations, single-point calculations of the total energies and atomic forces were performed within density functional theory using the CP2K Quickstep module. Reference calculations employed the revPBE-D3 and r2SCAN exchange-correlation functionals. Motivated by recent work on aqueous Zn²?, the main revPBE calculations omitted D3 dispersion contributions involving Zn²?, while retaining the D3 correction for water and chloride. For comparison, fully dispersion-corrected revPBE-D3 reference calculations were also performed, with D3 applied to all species, including Zn²?. Valence electrons were treated explicitly, while core electrons were represented using norm-conserving Goedecker–Teter–Hutter pseudopotentials. The wave functions were expanded using the mixed Gaussian-and-plane-wave scheme with TZV2P-MOLOPT basis sets for all elements and a 600 Ry auxiliary plane-wave cutoff for the electron density. Self-consistent-field convergence was accelerated using the orbital-transformation and Direct Inversion in the Iterative Subspace algorithms, with a convergence threshold of 10?6. All single-point calculations were performed in periodic orthorhombic cells. The CELL_REF keyword in CP2K was used to define a fixed reference cell with a box length of 25 Å. This treatment ensured a consistent reference for configurations extracted from NpT trajectories with fluctuating cell dimensions. The resulting DFT energies and atomic forces constitute the ground-truth labels used to train the MLIPs. The resulting MLIP was trained for aqueous ZnCl2 solutions spanning concentrations from 0 to 30 molal and a broad pH range, from strongly acidic to strongly basic conditions. Representative examples of configurations included in the MLIP training dataset are provided below. These include 1) Representative configurations from the dataset labeled at the revPBE-D3 level, with D3 dispersion interactions involving Zn2+ excluded (revPBE-wo-D3). 2) Representative configurations from the dataset labeled at the fully dispersion-corrected revPBE-D3 level, with D3 interactions applied to all species, including Zn2+ (revPBE-D3). 3) Representative configurations from the dataset labeled at the r2SCAN level of theory (r2SCAN).

Dinpajooh, Mohammadhasan [Pacific Northwest Nation↗