Benoit Roux
University of Chicago
H-index: 136
North America-United States
Description
Benoit Roux, With an exceptional h-index of 136 and a recent h-index of 66 (since 2020), a distinguished researcher at University of Chicago, specializes in the field of computations, membranes, proteins, structure, channels.
His recent articles reflect a diverse array of research interests and contributions to the field:
Classifying Protein-Protein Binding Affinity with Free-Energy Calculations and Machine Learning Approaches.
Configurational Sampling of All-Atom Solvated Membranes Using Hybrid Nonequilibrium Molecular Dynamics Monte Carlo Simulations
Classifying Protein–Protein Binding Affinity with Free-Energy Calculations and Machine Learning Approaches
Computational Investigation of the Covalent Inhibition Mechanism of Bruton’s Tyrosine Kinase by Ibrutinib
How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?
Isoleucine gate blocks K+ conduction in C-type inactivation
Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Alchemical free-energy simulations support the formation of the sarco-endoplasmic reticulum calcium pump (SERCA) inhibitory complex from the phospholamban pentamer
Professor Information
University | University of Chicago |
---|---|
Position | Professor of Biochemistry The |
Citations(all) | 82566 |
Citations(since 2020) | 24636 |
Cited By | 69794 |
hIndex(all) | 136 |
hIndex(since 2020) | 66 |
i10Index(all) | 408 |
i10Index(since 2020) | 293 |
University Profile Page | University of Chicago |
Research & Interests List
computations
membranes
proteins
structure
channels
Top articles of Benoit Roux
Classifying Protein-Protein Binding Affinity with Free-Energy Calculations and Machine Learning Approaches.
Understanding the intricate phenomenon of neuronal wiring in the brain is of great interest in neuroscience. In the fruit fly, Drosophila melanogaster, the Dpr-DIP interactome has been identified to play an important role in this process. However, experimental data suggest that a merely limited subset of complexes, essentially 57 out of a total of 231, exhibit strong binding affinity. In this work, we sought to identify the residue-level molecular basis underlying the difference in binding affinity using a state-of-the-art methodology consisting of standard binding free-energy calculations with a geometrical route and machine learning (ML) techniques. We determined the binding affinity for two complexes using statistical mechanics simulations, achieving an excellent reproduction of the experimental data. Moreover, we predicted the binding free energy for two additional low-affinity complexes, devoid of experimental estimation, while simultaneously identifying key residues for the binding. Furthermore, through the use of ML algorithms, linear discriminant analysis, and random forest, we achieved remarkable accuracy, as high as 0.99, in discerning between strong (cognate) and weak (noncognate) binders. The presented ML approach encompasses easily transferable input features, enabling its broad application to any interactome while facilitating the identification of pivotal residues critical for binding interactions. The predictive power of the generated model was probed on similar protein families from 13 diverse species. Our ML model exhibited commendable performance on these additional data sets, showcasing its reliability and robustness across the …
Authors
B Roux,C Chipot
Journal
Journal of Chemical Information and Modeling
Published Date
2024/1/25
Configurational Sampling of All-Atom Solvated Membranes Using Hybrid Nonequilibrium Molecular Dynamics Monte Carlo Simulations
All-atom simulations are a powerful approach to study the structure and dynamics of biological membranes. However, sampling the atomic configurations of inhomogeneous membranes can be challenging due to the slow lateral diffusion of the various constituents. To address this issue, a hybrid nonequilibrium molecular dynamics Monte Carlo (neMD/MC) simulation method is proposed in which randomly chosen lipid molecules are swapped to generate configurations that are subsequently accepted or rejected according to a Metropolis criterion based on the alchemical work for the attempted swap calculated via a short trajectory. A dual-topology framework constraining the common atoms of the exchanging molecules yields a good acceptance probability using switching trajectories as short as 10 ps. The performance of the hybrid neMD/MC algorithm and its ability to sample the distribution of lipids near a …
Authors
Florence Szczepaniak,François Dehez,Benoît Roux
Journal
The Journal of Physical Chemistry Letters
Published Date
2024/4/1
Classifying Protein–Protein Binding Affinity with Free-Energy Calculations and Machine Learning Approaches
Understanding the intricate phenomenon of neuronal wiring in the brain is of great interest in neuroscience. In the fruit fly, Drosophila melanogaster, the Dpr-DIP interactome has been identified to play an important role in this process. However, experimental data suggest that a merely limited subset of complexes, essentially 57 out of a total of 231, exhibit strong binding affinity. In this work, we sought to identify the residue-level molecular basis underlying the difference in binding affinity using a state-of-the-art methodology consisting of standard binding free-energy calculations with a geometrical route and machine learning (ML) techniques. We determined the binding affinity for two complexes using statistical mechanics simulations, achieving an excellent reproduction of the experimental data. Moreover, we predicted the binding free energy for two additional low-affinity complexes, devoid of experimental …
Authors
Emma Goulard Coderc de Lacam,Benoît Roux,Christophe Chipot
Journal
Journal of Chemical Information and Modeling
Published Date
2024/1/25
Computational Investigation of the Covalent Inhibition Mechanism of Bruton’s Tyrosine Kinase by Ibrutinib
Covalent inhibitors represent a promising class of therapeutic compounds. Nonetheless, rationally designing covalent inhibitors to achieve a right balance between selectivity and reactivity remains extremely challenging. To better understand the covalent binding mechanism, a computational study is carried out using the irreversible covalent inhibitor of Bruton tyrosine kinase (BTK) ibrutinib as an example. A multi-μs classical molecular dynamics trajectory of the unlinked inhibitor is generated to explore the fluctuations of the compound associated with the kinase binding pocket. Then, the reaction pathway leading to the formation of the covalent bond with the cysteine residue at position 481 via a Michael addition is determined using the string method in collective variables on the basis of hybrid quantum mechanical–molecular mechanical (QM/MM) simulations. The reaction pathway shows a strong correlation …
Authors
Angela M Barragan,Kyle Ghaby,Matthew P Pond,Benoît Roux
Journal
Journal of Chemical Information and Modeling
Published Date
2024/3/28
How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?
According to the pH-partition hypothesis, the aqueous solution adjacent to a membrane is a mixture of the ionization states of the permeating molecule at fixed Henderson–Hasselbalch concentrations, such that each state passes through the membrane in parallel with its own specific permeability. An alternative view, based on the assumption that the rate of switching ionization states is instantaneous, represents the permeation of ionizable molecules via an effective Boltzmann-weighted average potential (BWAP). Such an assumption is used in constant-pH molecular dynamics simulations. The inhomogeneous solubility-diffusion framework can be used to compute the pH-dependent membrane permeability for each of these two limiting treatments. With biased WTM-eABF molecular dynamics simulations, we computed the potential of mean force and diffusivity of each ionization state of two weakly basic small …
Authors
Jonathan Harris,Christophe Chipot,Benoît Roux
Journal
The Journal of Physical Chemistry B
Published Date
2024/1/16
Isoleucine gate blocks K+ conduction in C-type inactivation
Many voltage-gated potassium (Kv) channels display a time-dependent phenomenon called C-type inactivation, whereby prolonged activation by voltage leads to the inhibition of ionic conduction, a process that involves a conformational change at the selectivity filter toward a non-conductive state. Recently, a high-resolution structure of a strongly inactivating triple-mutant channel kv1.2-kv2.1-3m revealed a novel conformation of the selectivity filter that is dilated at its outer end, distinct from the well-characterized conductive state. While the experimental structure was interpreted as the elusive non-conductive state, molecular dynamics simulations and electrophysiology measurements demonstrate that the dilated filter of kv1.2-kv2.1-3m, however, is conductive and, as such, cannot completely account for the inactivation of the channel observed in functional experiments. An additional conformational change implicating isoleucine residues at position 398 along the pore lining segment S6 is required to effectively block ion conduction. It is shown that the I398 residues from the four subunits act as a state-dependent hydrophobic gate located immediately beneath the selectivity filter. As a critical piece of the C-type inactivation machinery, this structural feature is the potential target of a broad class of QA blockers and negatively charged activators thus opening new research directions towards the development of drugs that specifically modulate gating-states of Kv channels.
Authors
Werner Treptow,Yichen Liu,Carlos AZ Bassetto Jr,Bernardo I Pinto,João Alves,Christophe Chipot,Francisco Bezanilla,Benoît Roux
Journal
arXiv preprint arXiv:2403.16179
Published Date
2024/3/24
Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
The Ciona intestinalis voltage-sensing phosphatase (Ci-VSP) is a membrane protein containing a voltage-sensing domain (VSD) that is homologous to VSDs from voltage-gated ion channels responsible for cellular excitability. Previously published crystal structures of Ci-VSD in putative resting and active conformations suggested a helical-screw voltage sensing mechanism in which the S4 helix translocates and rotates to enable exchange of salt-bridge partners, but the microscopic details of the transition between the resting and active conformations remained unknown. Here, by combining extensive molecular dynamics simulations with a recently developed computational framework based on dynamical operators, we elucidate the microscopic mechanism of the resting-active transition at physiological membrane potential. Sparse regression reveals a small set of coordinates that distinguish intermediates that are …
Authors
Spencer C Guo,Rong Shen,Benoît Roux,Aaron R Dinner
Journal
Nature Communications
Published Date
2024/2/15
Alchemical free-energy simulations support the formation of the sarco-endoplasmic reticulum calcium pump (SERCA) inhibitory complex from the phospholamban pentamer
116a Sunday, February 11, 2024 in PLN (Ile18 to Leu52) for the SERCA-PLN complex, as well as the PLN monomer and pentamer in a lipid bilayer. We compared the simulation data to the functional analyses of the PLN alanine substitutions and their ability to inhibit SERCA. The PLN variants were classified as loss-of-function or gain-of-function in terms of their ability to alter the calcium affinity of SERCA (ie SERCA inhibition). Loss-of-function PLN variants do not inhibit SERCA and gain-of-function PLN variants are super-inhibitors of SERCA. For each PLN variant, changes in SERCA inhibition (KCa) were correlated with changes in free energy (DDG) for the formation of the SERCA-PLN complex from the PLN monomer or the PLN pentamer. The functional data were better explained by the formation of the SERCA-PLN complex directly from a PLN pentamer, where a PLN pentamer ‘‘delivers’’a PLN monomer to the …
Authors
Nishadh Rathod,Christophe J Chipot,Benoit Roux,Howard S Young
Journal
Biophysical Journal
Published Date
2024/2/8
Professor FAQs
What is Benoit Roux's h-index at University of Chicago?
The h-index of Benoit Roux has been 66 since 2020 and 136 in total.
What are Benoit Roux's top articles?
The articles with the titles of
Classifying Protein-Protein Binding Affinity with Free-Energy Calculations and Machine Learning Approaches.
Configurational Sampling of All-Atom Solvated Membranes Using Hybrid Nonequilibrium Molecular Dynamics Monte Carlo Simulations
Classifying Protein–Protein Binding Affinity with Free-Energy Calculations and Machine Learning Approaches
Computational Investigation of the Covalent Inhibition Mechanism of Bruton’s Tyrosine Kinase by Ibrutinib
How is Membrane Permeation of Small Ionizable Molecules Affected by Protonation Kinetics?
Isoleucine gate blocks K+ conduction in C-type inactivation
Dynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Alchemical free-energy simulations support the formation of the sarco-endoplasmic reticulum calcium pump (SERCA) inhibitory complex from the phospholamban pentamer
...
are the top articles of Benoit Roux at University of Chicago.
What are Benoit Roux's research interests?
The research interests of Benoit Roux are: computations, membranes, proteins, structure, channels
What is Benoit Roux's total number of citations?
Benoit Roux has 82,566 citations in total.
What are the co-authors of Benoit Roux?
The co-authors of Benoit Roux are Klaus Schulten, Emad Tajkhorshid, PhD, Francisco Bezanilla, Olaf S. Andersen, Wonpil Im, Chris Chipot.