Edward Harder
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View article: Accurate Hydration Free Energy Calculations for Diverse Organic Molecules With a Machine Learning Force Field
Accurate Hydration Free Energy Calculations for Diverse Organic Molecules With a Machine Learning Force Field Open
Free energy perturbation (FEP) calculations using classical force fields remain the dominant approach for large-scale, computational drug discovery efforts but the accuracy is fundamentally limited by simplified forms that cannot quantitat…
View article: A Method for Treating Significant Conformational Changes in Alchemical Free Energy Simulations of Protein–Ligand Binding
A Method for Treating Significant Conformational Changes in Alchemical Free Energy Simulations of Protein–Ligand Binding Open
Relative binding free energy (RBFE) simulation is a rigorous approach to the calculation of quantitatively accurate binding free energy values for protein-ligand binding in which a reference binder is gradually converted to a target binder…
View article: CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed
CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed Open
Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of…
View article: Accurate physics-based prediction of binding affinities of RNA and DNA targeting ligands
Accurate physics-based prediction of binding affinities of RNA and DNA targeting ligands Open
Accurate prediction of the affinity of ligand binding to nucleic acids represents a significant challenge for current computational approaches. This limitation has hindered the use of computational methods to develop small molecule drugs t…
View article: OPLS5: Addition of Polarizability and Improved Treatment of Metals
OPLS5: Addition of Polarizability and Improved Treatment of Metals Open
We report on the development and validation of the OPLS5 force field. OPLS5 further extends the accuracy of our previous model (OPLS4) with the addition of explicit polarization to improve model accuracy for molecular ions and cation-pi in…
View article: Accurate physics-based prediction of binding affinities of RNA and DNA targeting ligands
Accurate physics-based prediction of binding affinities of RNA and DNA targeting ligands Open
Accurate prediction of the affinity of ligand binding to nucleic acids represents a significant challenge for current computational approaches. This limitation has hindered the use of computational methods to develop small molecule drugs t…
View article: The maximal and current accuracy of rigorous protein-ligand binding free energy calculations
The maximal and current accuracy of rigorous protein-ligand binding free energy calculations Open
Computational techniques can speed up the identification of hits and accelerate the development of candidate molecules for drug discovery. Among techniques for predicting relative binding affinities, the most consistently accurate is free …
View article: The maximal and current accuracy of rigorous protein-ligand binding free energy calculations
The maximal and current accuracy of rigorous protein-ligand binding free energy calculations Open
It is now well recognized that computational techniques can greatly speed up the identification of hits and accelerate the optimization of such hits to lead series and development candidate molecules. In particular, a class of rigorous phy…
View article: The maximal and current accuracy of rigorous protein-ligand binding free energy calculations
The maximal and current accuracy of rigorous protein-ligand binding free energy calculations Open
It is well recognized that computational techniques can speed up the identification of hits and accelerate the optimization of such hits to lead series and development candidate molecules. A class of rigorous physics-based methods known as…
View article: The maximal and current accuracy of rigorous protein-ligand binding free energy calculations
The maximal and current accuracy of rigorous protein-ligand binding free energy calculations Open
It is now well recognized that computational techniques can greatly speed up the identification of hits and accelerate the optimization of such hits to lead series and development candidate molecules. In particular, a class of rigorous phy…
View article: Reliable and Accurate Prediction of Single Residue pKa Values Through Free Energy Perturbation Calculations
Reliable and Accurate Prediction of Single Residue pKa Values Through Free Energy Perturbation Calculations Open
Accurate prediction of the pKa’s of protein residues is crucial to many applications in biological simulation and drug discov-ery. Here we present the use of free energy perturbation (FEP) calculations for the prediction of single protein …
View article: Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo
Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo Open
The prediction of protein-ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations of prot…
View article: Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo
Enhancing Water Sampling in Free Energy Calculations with Grand Canonical Monte Carlo Open
The prediction of protein-ligand binding affinities using free energy perturbation (FEP) is becoming increasingly routine in structure-based drug discovery. Most FEP packages use molecular dynamics (MD) to sample the configurations of prot…
View article: Schrodinger-ANI: An Eight-Element Neural Network Interaction Potential with Greatly Expanded Coverage of Druglike Chemical Space
Schrodinger-ANI: An Eight-Element Neural Network Interaction Potential with Greatly Expanded Coverage of Druglike Chemical Space Open
We have developed a neural network potential energy function for use in drug discovery, with chemical element support extended from 41% to 94% of druglike molecules based on ChEMBL. We expand on the work of Smith et al., with their highly …
View article: Predicting Binding Affinities for GPCR Ligands Using Free-Energy Perturbation
Predicting Binding Affinities for GPCR Ligands Using Free-Energy Perturbation Open
The rapid growth of structural information for G-protein-coupled receptors (GPCRs) has led to a greater understanding of their structure, function, selectivity, and ligand binding. Although novel ligands have been identified using methods …
View article: How To Deal with Multiple Binding Poses in Alchemical Relative Protein–Ligand Binding Free Energy Calculations
How To Deal with Multiple Binding Poses in Alchemical Relative Protein–Ligand Binding Free Energy Calculations Open
Recent advances in improved force fields and sampling methods have made it possible for the accurate calculation of protein–ligand binding free energies. Alchemical free energy perturbation (FEP) using an explicit solvent model is one of t…