David L. Mobley
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View article: A Graph Neural Network Charge Model Targeting Accurate Electrostatic Properties of Organic Molecules
A Graph Neural Network Charge Model Targeting Accurate Electrostatic Properties of Organic Molecules Open
Common methods for assigning atom-centered partial charges in computational chemistry, such as RESP and AM1-BCC, rely on quantum mechanical or semiempirical calculations of the molecule of interest, which are expensive to compute and depen…
View article: A Polar Fullerene Model System for Benchmarking Enhanced Sampling of Trapped Waters in Free Energy Calculations
A Polar Fullerene Model System for Benchmarking Enhanced Sampling of Trapped Waters in Free Energy Calculations Open
Enhanced sampling methods, such as hybrid Monte Carlo/molecular dynamics (MC/MD), grand canonical MC/MD, non-equilibrium candidate MC/MD, etc., are widely used to sample slow rearrangement of water molecules in binding free energy calculat…
View article: Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters
Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters Open
The formation of protein-ligand complexes involves displacement of water molecules that were previously occupying the protein's binding site. In some cases, however, some water molecules may not be displaced by the ligand's binding, and th…
View article: Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A
Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A Open
Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the…
View article: Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters
Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters Open
The formation of protein-ligand complexes involves displacement of water molecules that were previously occupying the protein's binding site. In some cases, however, some water molecules may not be displaced by the ligand's binding and the…
View article: A graph neural network charge model targeting accurate electrostatic properties of organic molecules
A graph neural network charge model targeting accurate electrostatic properties of organic molecules Open
Common methods for assigning atom-centered partial charges in computational chemistry, such as RESP and AM1-BCC, rely on quantum mechanical or semi-empirical calculations of the molecule of interest, which are expensive to compute and depe…
View article: Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters
Advancing Binding Affinity Calculations: A Non-Equilibrium Simulations Approach for Calculation of Relative Binding Free Energies in Systems with Trapped Waters Open
The formation of protein-ligand complexes involves displacement of water molecules that were previously occupying the protein's binding site. In some cases, however, some water molecules may not be displaced by the ligand's binding and the…
View article: Evaluating the Functional Importance of Conformer‐Dependent Atomic Partial Charge Assignment
Evaluating the Functional Importance of Conformer‐Dependent Atomic Partial Charge Assignment Open
Physics‐based methods such as protein‐ligand binding free energy calculations have been increasingly adopted in early‐stage drug discovery to prioritize promising compounds for synthesis. However, the accuracy of these methods is highly de…
View article: IMERGE-FEP: Improving Relative Free Energy Calculation Convergence with Chemical Intermediates
IMERGE-FEP: Improving Relative Free Energy Calculation Convergence with Chemical Intermediates Open
Alchemical free energy calculations are becoming an increasingly prevalent tool in drug discovery efforts. Over the past decade, significant progress has been made in automating various aspects of this technique. However, one aspect hamper…
View article: Evaluating the functional importance of conformer-dependent atomic partial charge assignment
Evaluating the functional importance of conformer-dependent atomic partial charge assignment Open
Physics-based methods such as protein-ligand binding free energy calculations have been increasingly adopted in early-stage drug discovery to prioritize promising compounds for synthesis. However, the accuracy of these methods is highly de…
View article: Leveraging a Separation of States Method for Relative Binding Free Energy Calculations in Systems with Trapped Waters
Leveraging a Separation of States Method for Relative Binding Free Energy Calculations in Systems with Trapped Waters Open
Methods for calculating the relative binding free energy (RBFE) between ligands to a target protein are gaining importance in the structure-based drug discovery domain, especially as methodological advances and automation improve accuracy …
View article: Partially Sulfated Pillar[5]Arenes: Synthesis and Molecular Recognition Properties
Partially Sulfated Pillar[5]Arenes: Synthesis and Molecular Recognition Properties Open
We report the synthesis and characterization of sulfated pillar[5]arene hosts ( P5S 2 ‐P5S 10 ) that differ in the number of sulfate substituents. All five P5S n hosts display high solubility in water (73–131 mM) and do not undergo signifi…
View article: Kinetics-Based State Definitions for Discrete Binding Conformations of T4 L99A in MD via Markov State Modeling
Kinetics-Based State Definitions for Discrete Binding Conformations of T4 L99A in MD via Markov State Modeling Open
As a model system, the binding pocket of the L99A mutant of T4 lysozyme has been the subject of numerous computational free energy studies. However, previous studies have failed to fully sample and account for the observed changes in the b…
View article: Leveraging a separation of states method for relative binding free energy calculations in systems with trapped waters
Leveraging a separation of states method for relative binding free energy calculations in systems with trapped waters Open
Methods for calculating the relative binding free energy (RBFE) between ligands to a target protein are gaining importance in the structure-based drug discovery domain, especially as methodological advances and automation improve accuracy …
View article: Konnektor: A Framework for Using Graph Theory to Plan Networks for Free Energy Calculations
Konnektor: A Framework for Using Graph Theory to Plan Networks for Free Energy Calculations Open
Alchemical free energy campaigns can be planned using graph theory by building networks that contain nodes representing molecules that are connected by possible transformations as edges. We introduce Konnektor, an open-source Python packag…
View article: alchemlyb: the simple alchemistry library
alchemlyb: the simple alchemistry library Open
alchemlyb is an open-source Python software package for the analysis of alchemical free energy calculations, an important method in computational chemistry and biology, most notably in the field of drug discovery (Merz et al., 2010). Its f…
View article: Konnektor: A framework for using graph theory to plan networks for free energy calculations
Konnektor: A framework for using graph theory to plan networks for free energy calculations Open
Alchemical free energy campaigns can be planned using graph theory by building up networks that contain nodes representing molecules that are connected by possible transformations as edges. We introduce Konnektor, an open-source Python pac…
View article: Leveraging a separation of states method for relative binding free energy calculations in systems with trapped waters
Leveraging a separation of states method for relative binding free energy calculations in systems with trapped waters Open
Methods for calculating the relative binding free energy (RBFE) between ligands to a target protein are gaining importance in the structure-based drug discovery domain, especially as methodological advances and automation improve accuracy …
View article: Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields
Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields Open
A wide range of density functional methods and basis sets are available to derive the electronic structure and properties of molecules. Quantum mechanical calculations are too computationally intensive for routine simulation of molecules i…
View article: The Open Force Field Initiative: Open Software and Open Science for Molecular Modeling
The Open Force Field Initiative: Open Software and Open Science for Molecular Modeling Open
Force fields are a key component of physics-based molecular modeling, describing the energies and forces in a molecular system as a function of the positions of the atoms and molecules involved. Here, we provide a review and scientific sta…
View article: Current State of Open Source Force Fields in Protein–Ligand Binding Affinity Predictions
Current State of Open Source Force Fields in Protein–Ligand Binding Affinity Predictions Open
In drug discovery, the in silico prediction of binding affinity is one of the major means to prioritize compounds for synthesis. Alchemical relative binding free energy (RBFE) calculations based on molecular dynamics (MD) simulations are n…
View article: Building Block-Centric Approach to DNA-Encoded Library Design
Building Block-Centric Approach to DNA-Encoded Library Design Open
DNA-encoded library technology grants access to nearly infinite opportunities to explore the chemical structure space for drug discovery. Successful navigation depends on the design and synthesis of libraries with appropriate physicochemic…
View article: Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields
Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields Open
A wide range of density functional methods and basis sets are available to derive the electronic structure and properties of molecules. Quantum mechanical calculations are too computationally intensive for routine simulation of molecules i…
View article: Impact of protein conformations on binding free energy calculations in the beta‐secretase 1 system
Impact of protein conformations on binding free energy calculations in the beta‐secretase 1 system Open
In binding free energy calculations, simulations must sample all relevant conformations of the system in order to obtain unbiased results. For instance, different ligands can bind to different metastable states of a protein, and if these p…
View article: Characterizing Discrete Binding Conformations of T4 L99A via Markov State Modeling
Characterizing Discrete Binding Conformations of T4 L99A via Markov State Modeling Open
As a model system, the binding pocket of the L99A mutant of T4 lysozyme has been the subject of numerous computational free energy studies. However, some previous studies have failed to fully sample and account for the observed changes in …
View article: Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields
Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields Open
A wide range of density functional methods and basis sets are available to derive the electronic structure and properties of molecules. Quantum mechanical calculations are too computationally intensive for routine simulation of molecules i…
View article: Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields
Benchmarking Quantum Mechanical Levels of Theory for Valence Parametrization in Force Fields Open
A wide range of density functional methods and basis sets are available to derive the electronic structure and properties of molecules. Quantum mechanical calculations are too computationally intensive for routine simulation of molecules i…