Optimal Molecular Design: Generative Active Learning Combining REINVENT with Precise Binding Free Energy Ranking Simulations.

Active learning (AL) is a specific instance of sequential experimental design and uses machine learning to intelligently choose the next data point or batch of molecular structures to be evaluated. In this sense, it closely mimics the iterative design-make-test-analysis cycle of laboratory experiments to find optimized compounds for a given design task. Here, we describe an AL protocol which combines generative molecular AI, using REINVENT, and physics-based absolute binding free energy molecular dynamics simulation, using ESMACS, to discover new ligands for two different target proteins, 3CL and TNKS2.

Reinvent 4: Modern AI-driven generative molecule design.

REINVENT 4 is a modern open-source generative AI framework for the design of small molecules. The software utilizes recurrent neural networks and transformer architectures to drive molecule generation. These generators are seamlessly embedded within the general machine learning optimization algorithms, transfer learning, reinforcement learning and curriculum learning.

Reproducibility of Free Energy Calculations across Different Molecular Simulation Software Packages.

Alchemical free energy calculations are an increasingly important modern simulation technique to calculate free energy changes on binding or solvation. Contemporary molecular simulation software such as AMBER, CHARMM, GROMACS, and SOMD include support for the method. Implementation details vary among those codes, but users expect reliability and reproducibility, i.

Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database.

Solvation free energies can now be calculated precisely from molecular simulations, providing a valuable test of the energy functions underlying these simulations. Here, we briefly review "alchemical" approaches for calculating the solvation free energies of small, neutral organic molecules from molecular simulations, and illustrate by applying them to calculate aqueous solvation free energies (hydration free energies). These approaches use a non-physical pathway to compute free energy differences from a simulation or set of simulations and appear to be a particularly robust and general-purpose approach for this task.

Evaluation of Selected Classical Force Fields for Alchemical Binding Free Energy Calculations of Protein-Carbohydrate Complexes.

Protein-carbohydrate recognition is crucial in many vital biological processes including host-pathogen recognition, cell-signaling, and catalysis. Accordingly, computational prediction of protein-carbohydrate binding free energies is of enormous interest for drug design. However, the accuracy of current force fields (FFs) for predicting binding free energies of protein-carbohydrate complexes is not well understood owing to technical challenges such as the highly polar nature of the complexes, anomerization, and conformational flexibility of carbohydrates.

FESetup: Automating Setup for Alchemical Free Energy Simulations.

FESetup is a new pipeline tool which can be used flexibly within larger workflows. The tool aims to support fast and easy setup of alchemical free energy simulations for molecular simulation packages such as AMBER, GROMACS, Sire, or NAMD. Post-processing methods like MM-PBSA and LIE can be set up as well.

Ligand binding and dynamics of the monomeric epidermal growth factor receptor ectodomain.

The ectodomain of the human epidermal growth factor receptor (hEGFR) controls input to several cell signalling networks via binding with extracellular growth factors. To gain insight into the dynamics and ligand binding of the ectodomain, the hEGFR monomer was subjected to molecular dynamics simulation. The monomer was found to be substantially more flexible than the ectodomain dimer studied previously.

Human epidermal growth factor receptor (EGFR) aligned on the plasma membrane adopts key features of Drosophila EGFR asymmetry.

The ability of epidermal growth factor receptor (EGFR) to control cell fate is defined by its affinity for ligand. Current models suggest that ligand-binding heterogeneity arises from negative cooperativity in signaling receptor dimers, for which the asymmetry of the extracellular region of the Drosophila EGFR has recently provided a structural basis. However, no asymmetry is apparent in the isolated extracellular region of the human EGFR.

Collective dynamics of periplasmic glutamine binding protein upon domain closure.

The glutamine binding protein is a vital component of the associated ATP binding cassette transport systems responsible for the uptake of glutamine into the cell. We have investigated the global movements of this protein by molecular dynamics simulations and principal component analysis (PCA). We confirm that the most dominant mode corresponds to the biological function of the protein, i.

Ectodomain orientation, conformational plasticity and oligomerization of ErbB1 receptors investigated by molecular dynamics.

Epidermal growth factor receptor (EGFR; ErbB1, HER1 in humans) is a receptor tyrosine kinase triggering signals across the plasma membranes of cells to determine cell fate. We have used molecular dynamics simulations to investigate structural models of ErbB1 ectodomains. We show that, with minor rearrangements, the ErbB1 back-to-back dimer can align almost flat on the cell membrane.

Water exchange dynamics of lithium(I) ion in aqueous solution.

The water exchange dynamics of the fourfold coordinated first hydration shell of the lithium(I) ion was studied by both direct and umbrella sampling QM/MM-MD and classical MD simulations. The structural changes and energetics accompanying the activation process are discussed. The overall exchange rate constant was found to be k(ex) = 5.

Influence of backbone conformations of human carbonic anhydrase II on carbon dioxide hydration: hydration pathways and binding of bicarbonate.

In this study, the hydration of carbon dioxide and the formation of bicarbonate in human carbonic anhydrase II have been examined. From semiempirical QM/MM molecular dynamics studies, dominant conformations of the protein backbone, possibly contributing to the catalytic activity, have been isolated and further examined by means of density functional QM/MM methods. In agreement with experimental observations, a binding site for cyanate, which acts as an inhibitor, has been located, whereas for carbon dioxide, depending on the conformation of the protein environment, either a different binding site or no binding site has been found.

A QM-MM interface between CHARMM and TURBOMOLE: implementation and application to systems in bulk phase and biologically active systems.

The implementation of a hybrid QM-MM approach combining ab initio and density functional methods of TURBOMOLE with the molecular mechanics program package CHARMM is described. An interface has been created to allow data exchange between the two applications. With this method the efficient multiprocessor capabilities of TURBOMOLE can be utilized with CHARMM running as a single processor application.

Many-body effects on structure and dynamics of aqueous ionic solutions.

We performed several molecular dynamic studies of metal cations in aqueous solution. The alkali metal ion Li(+) and the first-row transition metal ion Mn(2+) have been chosen as model systems. Two different three-body corrections are proposed to mimic the crucial many-body effects of electrolyte solutions.

Structure and dynamics of metal ions in solution: QM/MM molecular dynamics simulations of Mn(2+) and V(2+).

Structural and dynamical properties of the transition metal ions V(2+) and Mn(2+) in aqueous solution, resulting from combined quantum mechanical (QM)/molecular mechanical (MM) molecular dynamics (MD) simulations have been compared. The necessity of polarization functions on the ligand's oxygen for a satisfactory description of such ions in aqueous solution is shown using V(2+) as test case. Radial distribution functions, coordination number distributions, and several angle distributions were pursued for a detailed structural comparison of the first hydration shells.