Bert L. de Groot
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View article: Atomistic Mechanism of Calcium-Mediated Inward Rectification of the MthK Potassium Channel by Solid-State NMR and MD Simulations
Atomistic Mechanism of Calcium-Mediated Inward Rectification of the MthK Potassium Channel by Solid-State NMR and MD Simulations Open
Inward rectification is a fundamental but poorly understood phenomenon in potassium channel physiology. Despite its physiological importance, the exact mechanism has remained elusive. In this work, we uncover a previously unrecognized calc…
View article: Evaluation of the ABCG2 Charge Model in Protein–Ligand Binding Free-Energy Calculations
Evaluation of the ABCG2 Charge Model in Protein–Ligand Binding Free-Energy Calculations Open
Accurate binding free energy prediction is vital for drug design, motivating the assessment of new force field models. Here, we evaluate the ABCG2 charge model with nonequilibrium alchemical free-energy simulations. GAFF2/ABCG2 achieves hi…
View article: Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation
Anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation Open
Alzheimer’s disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ)…
View article: Evaluation of the ABCG2 charge model in protein–ligand binding affinity calculations
Evaluation of the ABCG2 charge model in protein–ligand binding affinity calculations Open
Accurate binding free energy prediction is vital for drug design, motivating the assessment of new force field models. Here, we evaluate the ABCG2 charge model with nonequilibrium alchemical free energy simulations. GAFF2/ABCG2 achieves hi…
View article: Evaluation of the ABCG2 charge model in protein–ligand binding affinity calculations
Evaluation of the ABCG2 charge model in protein–ligand binding affinity calculations Open
Accurate binding free energy prediction is vital for drug design, motivating the assessment of new force field models. Here, we evaluate the ABCG2 charge model with nonequilibrium alchemical free energy simulations. GAFF2/ABCG2 achieves hi…
View article: Atomistic Mechanism of Calcium-Mediated Inward Rectification of the MthK Potassium Channel by Solid-State NMR and MD Simulations
Atomistic Mechanism of Calcium-Mediated Inward Rectification of the MthK Potassium Channel by Solid-State NMR and MD Simulations Open
Inward rectification is a fundamental but poorly understood phenomenon in potassium channel physiology. Despite its physiological importance, the exact mechanism has remained elusive. In this work, we uncover a previously unrecognized calc…
View article: Quantification of the Impact of Structure Quality on Predicted Binding Free Energy Accuracy
Quantification of the Impact of Structure Quality on Predicted Binding Free Energy Accuracy Open
Relative binding free energy (RBFE) calculations have emerged as a powerful tool in drug discovery, capable of achieving experimental-level accuracy. However, the accuracy is compromised by a multitude of factors, including the initial str…
View article: The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation.
The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation. Open
Alzheimer’s disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ)…
View article: The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation
The clinical drug candidate anle138b binds predominantly to the central cavity in lipidic Aβ₄₀ fibrils and modulates fibril formation Open
Alzheimer’s disease is a specific neurodegenerative disorder, distinct from normal aging, with a growing unmet medical need. It is characterized by the accumulation of amyloid plaques in the brain, primarily consisting of amyloid beta (Aβ)…
View article: Effective polarization in potassium channel simulations: Ion conductance, occupancy, voltage response, and selectivity
Effective polarization in potassium channel simulations: Ion conductance, occupancy, voltage response, and selectivity Open
Potassium (K + ) channels are widely distributed in many types of organisms. They combine high efficiency (~100 pS) and K + /Na + selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed,…
View article: Free energy calculations for protein design
Free energy calculations for protein design Open
Free energy calculations have become invaluable in protein design, offering a powerful means to rapidly and accurately screen potential variants. Here, we provide a step-by-step protocol that combines molecular dynamics simulations with no…
View article: Free Energy Simulations to Quantitatively Study Biomolecule Stability and Binding
Free Energy Simulations to Quantitatively Study Biomolecule Stability and Binding Open
Free energy calculations based on molecular dynamics simulations offer a quantitative assessment of biomolecule binding and stability. This chapter discusses accurately estimating the free energy differences employing nonequilibrium alchem…
View article: Improving p <i>K</i> <sub>a</sub> Predictions with Reparameterized Force Fields and Free Energy Calculations
Improving p <i>K</i> <sub>a</sub> Predictions with Reparameterized Force Fields and Free Energy Calculations Open
Given the growing interest in designing targeted covalent inhibitors, methods for rapidly and accurately probing pKas─and, by extension, the reactivities─of target cysteines are highly desirable. Complementary to cysteine…
View article: The need to implement FAIR principles in biomolecular simulations
The need to implement FAIR principles in biomolecular simulations Open
International audience
View article: Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding
Prospective Evaluation of Structure-Based Simulations Reveal Their Ability to Predict the Impact of Kinase Mutations on Inhibitor Binding Open
Small molecule kinase inhibitors are critical in the modern treatment of cancers, evidenced by the existence of over 80 FDA-approved small-molecule kinase inhibitors. Unfortunately, intrinsic or acquired resistance, often causing therapy d…
View article: Scaling of the GROMACS Molecular Dynamics Code to 65k CPU Cores on an HPC Cluster
Scaling of the GROMACS Molecular Dynamics Code to 65k CPU Cores on an HPC Cluster Open
We benchmarked the performance of the GROMACS 2024 molecular dynamics (MD) code on a modern high‐performance computing (HPC) cluster with AMD CPUs on up to 65,536 CPU cores. We used five different MD systems, ranging in size from about 82,…
View article: Lipidic folding pathway of α-Synuclein via a toxic oligomer
Lipidic folding pathway of α-Synuclein via a toxic oligomer Open
Aggregation intermediates play a pivotal role in the assembly of amyloid fibrils, which are central to the pathogenesis of neurodegenerative diseases. The structures of filamentous intermediates and mature fibrils are now efficiently deter…
View article: Improving pKa prediction accuracy with reparametrized force fields and free energy calculations
Improving pKa prediction accuracy with reparametrized force fields and free energy calculations Open
Given the growing interest in designing targeted covalent inhibitors, methods for rapidly and accurately probing pKas—and, by extension, the reactivities—of target cysteines is highly desirable. Complementary to cysteine, histidine is simi…
View article: NOMPC ion channel hinge forms a gating spring that initiates mechanosensation
NOMPC ion channel hinge forms a gating spring that initiates mechanosensation Open
The sensation of mechanical stimuli is initiated by elastic gating springs that pull open mechanosensory transduction channels. Searches for gating springs have focused on force-conveying protein tethers such as the amino-terminal ankyrin …
View article: Identification of allosteric sites and ligand-induced modulation in the dopamine receptor through large-scale alchemical mutation scan
Identification of allosteric sites and ligand-induced modulation in the dopamine receptor through large-scale alchemical mutation scan Open
Using alchemical free energy simulations, we identify allosteric residues in DRD2 that modulate activation. Mutation-induced network changes reveal mechanisms of state stabilization and enable selective ligand design, exemplified by two kn…
View article: From Selective Permeation to Physiology in Potassium Channels
From Selective Permeation to Physiology in Potassium Channels Open
Highly K+-selective potassium channels are essential for electrical signaling. The high selectivity of most K+ channels, with relative K+: Na+ permeabilities being as high as 100–1000:1 arises from the conserved so-called K+ channel select…
View article: Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding
Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding Open
Small molecule kinase inhibitors are critical in the modern treatment of cancers, evidenced by the existence of over 80 FDA-approved small-molecule kinase inhibitors. Unfortunately, intrinsic or acquired resistance, often causing therapy d…
View article: Cysteine and histidine pKa prediction: alchemical free energy calculations and force field reparameterization
Cysteine and histidine pKa prediction: alchemical free energy calculations and force field reparameterization Open
Given the growing interest in designing targeted covalent inhibitors, methods for rapidly and accurately probing pKas—and, by extension, the reactivities—of target cysteines is highly desirable. Complementary to cysteine, histidine is simi…
View article: Effective Polarization in Potassium Channel Simulations: Ion Conductance, Occupancy, Voltage Response, and Selectivity
Effective Polarization in Potassium Channel Simulations: Ion Conductance, Occupancy, Voltage Response, and Selectivity Open
Potassium (K + ) channels are widely distributed in many types of organisms. They combine high efficiency (∼100 pS) and K + /Na + selectivity by a conserved selectivity filter (SF). Molecular Dynamics (MD) simulations can provide detailed,…
View article: Author response: Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts
Author response: Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts Open
View article: Effect of two activators on the gating of a K2P channel
Effect of two activators on the gating of a K2P channel Open
TWIK-related potassium channel 1 (TREK1), a two-pore-domain mammalian potassium (K+) channel, regulates the resting potential across cell membranes, presenting a promising therapeutic target for neuropathy treatment. The gating …
View article: Biomolecular simulations at the exascale: From drug design to organelles and beyond
Biomolecular simulations at the exascale: From drug design to organelles and beyond Open
The rapid advancement in computational power available for research offers to bring not only quantitative improvements, but also qualitative changes in the field of biomolecular simulation. Here, we review the state of biomolecular dynamic…
View article: Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts
Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts Open
Aquaporin-0 (AQP0) tetramers form square arrays in lens membranes through a yet unknown mechanism, but lens membranes are enriched in sphingomyelin and cholesterol. Here, we determined electron crystallographic structures of AQP0 in sphing…
View article: Selectivity filter mutations shift ion permeation mechanism in potassium channels
Selectivity filter mutations shift ion permeation mechanism in potassium channels Open
Potassium (K+) channels combine high conductance with high ion selectivity. To explain this efficiency, two molecular mechanisms have been proposed. The “direct knock-on” mechanism is defined by water-free K+ permeation and formation of di…
View article: Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts
Structure and dynamics of cholesterol-mediated aquaporin-0 arrays and implications for lipid rafts Open
Aquaporin-0 (AQP0) tetramers form square arrays in lens membranes through a yet unknown mechanism, but lens membranes are enriched in sphingomyelin and cholesterol. Here, we determined electron crystallographic structures of AQP0 in sphing…