The implicit solvent approach offers a computationally efficient framework to model solvation effects in molecular simulations. However, its accuracy often falls short compared to explicit solvent models, limiting its use in precise thermodynamic calculations. Recent advancements in machine learning (ML) present an opportunity to overcome these limitations by leveraging neural networks to develop more precise implicit solvent potentials for diverse applications. A major drawback of current ML-based methods is their reliance on force-matching alone, which can lead to energy predictions that differ by an arbitrary constant and are therefore unsuitable for absolute free energy comparisons. Here, we introduce a novel methodology with a graph neural network (GNN)-based implicit solvent model, dubbed Lambda Solvation Neural Network (LSNN). In addition to force-matching, this network was trained to match the derivatives of alchemical variables, ensuring that solvation free energies can be meaningfully compared across chemical species.. Trained on a dataset of approximately 300,000 small molecules, LSNN achieves free energy predictions with accuracy comparable to explicit-solvent alchemical simulations, while offering a computational speedup and establishing a foundational framework for future applications in drug discovery.

Crystal Structure Prediction (CSP) of molecular crystals plays a central role in applications, such as pharmaceuticals and organic electronics. CSP is challenging and computationally expensive due to the need to explore a large search space with sufficient accuracy to capture energy differences of a few kJ/mol between polymorphs. Dispersion-inclusive density functional theory (DFT) provides the required accuracy but its computational cost is impractical for a large number of putative structures. We introduce FastCSP, an open-source, high-throughput CSP workflow based on machine learning interatomic potentials (MLIPs). FastCSP combines random structure generation using Genarris 3.0 with geometry relaxation and free energy calculations powered entirely by the Universal Model for Atoms (UMA) MLIP. We benchmark FastCSP on a curated set of 28 mostly rigid molecules, demonstrating that our workflow consistently generates known experimental structures and ranks them within 5 kJ/mol per molecule of the global minimum. Our results demonstrate that universal MLIPs can be used across diverse compounds without requiring system-specific tuning. Moreover, the speed and accuracy afforded by UMA eliminate the need for classical force fields in the early stages of CSP and for final re-ranking with DFT. The open-source release of the entire FastCSP workflow significantly lowers the barrier to accessing CSP. CSP results for a single system can be obtained within hours on tens of modern GPUs, making high-throughput crystal structure prediction feasible for a broad range of scientific applications.

The Targeted Free Energy Perturbation (TFEP) method aims to overcome the time-consuming and computer-intensive stratification process of standard methods for estimating the free energy difference between two states. To achieve this, TFEP uses a mapping function between the high-dimensional probability densities of these states. The bijectivity and invertibility of normalizing flow neural networks fulfill the requirements for serving as such a mapping function. Despite its theoretical potential for free energy calculations, TFEP has not yet been adopted in practice due to challenges in entropy correction, limitations in energy-based training, and mode collapse when learning density functions of larger systems with a high number of degrees of freedom. In this study, we expand flow-based TFEP to systems with variable number of atoms in the two states of consideration by exploring the theoretical basis of entropic contributions of dummy atoms, and validate our reasoning with analytical derivations for a model system containing coupled particles. We also extend the TFEP framework to handle systems of hybrid topology, propose auxiliary additions to improve the TFEP architecture, and demonstrate accurate predictions of relative free energy differences for large molecular systems. Our results provide the first practical application of the fast and accurate deep learning-based TFEP method for biomolecules and introduce it as a viable free energy estimation method within the context of drug design.

Automated free energy calculations for the prediction of binding free energies of congeneric series of ligands to a protein target are growing in popularity, but building reliable initial binding poses for the ligands is challenging. Here, we introduce the open-source FEgrow workflow for building user-defined congeneric series of ligands in protein binding pockets for input to free energy calculations. For a given ligand core and receptor structure, FEgrow enumerates and optimises the bioactive conformations of the grown functional group(s), making use of hybrid machine learning/molecular mechanics potential energy functions where possible. Low energy structures are optionally scored using the gnina convolutional neural network scoring function, and output for more rigorous protein–ligand binding free energy predictions. We illustrate use of the workflow by building and scoring binding poses for ten congeneric series of ligands bound to targets from a standard, high quality dataset of protein–ligand complexes. Furthermore, we build a set of 13 inhibitors of the SARS-CoV-2 main protease from the literature, and use free energy calculations to retrospectively compute their relative binding free energies. FEgrow is freely available at https://github.com/cole-group/FEgrow , along with a tutorial. Automated free energy calculations for the prediction of binding free energies of ligands to a protein target are gaining importance for drug discovery, but building reliable initial binding poses for the ligands is challenging. Here, the authors introduce an open-source workflow for building user-defined congeneric series of ligands in protein binding pockets for input to free energy calculations.

Lawrence Livermore National Laboratory (LLNL) researchers have identified an initial set of therapeutic antibody sequences, designed in a few weeks using machine learning and supercomputing, aimed at binding and neutralizing SARS-CoV-2, the virus that causes COVID-19. The research team is performing experimental testing on the chosen antibody designs. Currently, treating COVID-19 with antibodies is only possible by harvesting them from the blood of patients who have fully recovered. As the new antibody designs are improved through an iterative computational-experimental process, they could enable a safer, more reliable and scalable pathway to using antibodies as potential treatments for people stricken with the disease, scientists said. In a paper appearing on the open access preprint website BioRxiv--which has not been peer-reviewed--LLNL scientists describe how they used the Lab's high performance computers and a machine learning-driven computational platform to design antibody candidates predicted to bind with SARS-CoV-2 Receptor Binding Domain (RBD).