Louis Lagardère

Louis Lagardère
Sorbonne Université | UPMC · Laboratoire de chimie théorique (LCT) - UMR 7616

PhD

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96
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2,098
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Publications

Publications (96)
Preprint
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Acetylcholinesterase is one of the most significant known serine hydrolases, governing the mammalian nervous system. Its high rate speed, operating at the diffusion limit, combined with its buried active site feature, has made it a subject of extensive research over the last decades. Despite several studies focused on atomistic details of its diffe...
Article
We derive and implement an alternative formulation of the Stochastic Lanczos algorithm to be employed in connection with the Many-Body Dispersion model (MBD). Indeed, this formulation, which is only possible due to the Stochastic Lanczos’ reliance on matrix-vector products, introduces generalized dipoles and fields. These key quantities allow for a...
Article
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We introduce FENNIX (Force-Field-Enhanced Neural Network InteraXions), a hybrid approach between machine-learning and force-fields. We leverage state-of-the-art equivariant neural networks to predict local energy contributions and multiple atom-in-molecule properties that are then used as geometry-dependent parameters for physically-motivated energ...
Preprint
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Bisacridinyl-bisarginyl porphyrin (BABAP) is a trisintercalating derivative of a tricationic porphyrin, formerly designed and synthesized in order to selectively target and photosensitize the ten-base pair palindromic sequence d(CGGGCGCCCG)2. We resorted to the previously derived (Far et al., 2004) lowest energy-minimized (EM) structure of the BABA...
Preprint
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We introduce an efficient and robust method to compute alchemical free energy differences, resulting from the application of multiple walker Adaptive Biasing Force (ABF) in conjunction with strongly damped Langevin lambda-dynamics. Unbiased alchemical free energy surfaces are naturally recovered by Thermodynamic Integration (TI). No manual optimiza...
Preprint
Full-text available
We derive and implement an alternative formulation of the Stochastic Lanczos algorithm to be employed in connection with the Many-Body Dispersion model (MBD). Indeed, this formulation, which is only possible due to the Stochastic Lanczos' reliance on matrix-vector products, introduces generalized dipoles and fields. These key quantities allow for a...
Article
Full-text available
We describe the development, implementation, and application of a polarizable QM/MM strategy, based on the AMOEBA polarizable force field, for calculating molecular properties and performing dynamics of molecular systems embedded in complex matrices. We show that polarizable QM/MM is a well‐understood, mature technology that can be deployed using a...
Article
To evaluate electrostatics interactions, molecular dynamics (MD) simulations rely on Particle Mesh Ewald (PME), an 𝒪(𝑁log(𝑁)) algorithm that uses Fast Fourier Transforms (FFTs) or, alternatively, on 𝒪(𝑁) Fast Multipole Methods (FMM) approaches. However, the FFTs low scalability remains a strong bottleneck for large-scale PME simulations on supercom...
Article
Full-text available
Deep-HP is a scalable extension of the Tinker-HP multi-GPUs molecular dynamics (MD) package enabling the use of Pytorch/TensorFlow Deep Neural Networks (DNNs) models. Deep-HP increases DNNs MD capabilities by orders of magnitude offering access to ns simulations for 100k-atom biosystems while offering the possibility of coupling DNNs to any classic...
Article
We report the implementation of a multi-CPU and multi-GPU massively parallel platform dedicated to the explicit inclusion of nuclear quantum effects (NQEs) in the Tinker-HP molecular dynamics (MD) package. The platform, denoted Quantum-HP, exploits two simulation strategies: the Ring-Polymer Molecular Dynamics (RPMD) that provides exact structural...
Article
Full-text available
We extend our recently proposed Deep Learning-aided many-body dispersion (DNN-MBD) model to quadrupole polarizability (Q) terms using a generalized Random Phase Approximation (RPA) formalism, thus enabling the inclusion of van der Waals contributions beyond dipole. The resulting DNN-MBDQ model only relies on ab initio-derived quantities as the intr...
Preprint
Full-text available
We introduce FENNIX (Force-Field-Enhanced Neural Network InteraXions), a hybrid approach between machine-learning and force-fields. We leverage state-of-the-art equivariant neural networks to predict local energy contributions and multiple atom-in-molecule properties that are then used as geometry-dependent parameters for physically-motivated energ...
Preprint
Full-text available
Actin undergoes important structural changes to transition from the G-actin to the F-actin form. Furthermore, mammals express different isoforms, with only slight variations at the amino acid level. While the 𝛼-skeletal actin isoform was thoroughly studied using molecular dynamics simulations, the dynamics of the 𝛽-actin isoform remains unexplored....
Preprint
Full-text available
To evaluate electrostatics interactions, Molecular dynamics (MD) simulations rely on Particle Mesh Ewald (PME), an O(Nlog(N)) algorithm that uses Fast Fourier Transforms (FFTs) or, alternatively, on O(N) Fast Multipole Methods (FMM) approaches. However, the FFTs low scalability remains a strong bottleneck for large-scale PME simulations on supercom...
Preprint
Full-text available
We extend our recently proposed Deep Learning-aided many-body dispersion (DNN-MBD) model to quadrupole polarizability (Q) terms using a generalized Random Phase Approximation (RPA) formalism, thus enabling the inclusion of van der Waals contributions beyond dipole. The resulting DNN-MBDQ model only relies on ab initio-derived quantities as the intr...
Preprint
Full-text available
We report the implementation of a multi-CPU and multi-GPU massively parallel platform dedicated to the explicit inclusion of nuclear quantum effects (NQEs) in the Tinker-HP molecular dynamics (MD) package. The platform, denoted Quantum-HP, exploits two simulation strategies: the Ring-Polymer Molecular Dynamics (RPMD) that provides exact structural...
Article
We introduce a new parametrization of the AMOEBA polarizable force field for water denoted Q-AMOEBA, for use in simulations that explicitly account for nuclear quantum effects (NQEs). This study is made possible thanks to the recently introduced adaptive Quantum Thermal Bath (adQTB) simulation technique which computational cost is comparable to cla...
Preprint
Full-text available
We introduce a new parametrization of the AMOEBA polarizable force field for water denoted Q-AMOEBA, for use in simulations that explicitly account for nuclear quantum effects (NQEs). This study is made possible thanks to the recently introduced adaptive Quantum Thermal Bath (adQTB) simulation technique which computational cost is comparable to cla...
Preprint
Full-text available
Deep-HP is a scalable extension of the \TinkerHP\ multi-GPUs molecular dynamics (MD) package enabling the use of Pytorch/TensorFlow Deep Neural Networks (DNNs) models. Deep-HP increases DNNs MD capabilities by orders of magnitude offering access to ns simulations for 100k-atom biosystems while offering the possibility of coupling DNNs to any classi...
Article
GC-rich sequences are recurring motifs in oncogenes and retroviruses and could be targeted by noncovalent major-groove therapeutic ligands. We considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several oligopeptide derivatives of the anticancer intercalator mitoxantrone. The stability of their complexes with an 18-mer oligonucleotid...
Article
We present the extension of the Sum of Interactions Between Fragments Ab initio Computed (SIBFA) many-body polarizable force field to condensed-phase molecular dynamics (MD) simulations. The quantum-inspired SIBFA procedure is grounded on simplified integrals obtained from localized molecular orbital theory and achieves full separability of its int...
Article
Using a deep neuronal network (DNN) model trained on the large ANI-1 data set of small organic molecules, we propose a transferable density-free many-body dispersion (DNN-MBD) model. The DNN strategy bypasses the explicit Hirshfeld partitioning of the Kohn-Sham electron density required by MBD models to obtain the atom-in-molecules volumes used by...
Cover Page
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We report a fast-track computationally driven discovery of new SARS-CoV-2 main protease (Mpro) inhibitors whose potency ranges from mM for the initial non-covalent ligands to sub-μM for the final covalent compound (IC50 = 830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding fre...
Preprint
Full-text available
Using a Deep Neuronal Network model (DNN) trained on the large ANI-1 data set of small organic molecules, we propose a transferable density-free many-body dispersion model (DNN-MBD). The DNN strategy bypasses the explicit Hirshfeld partitioning of the Kohn-Sham electron density required by MBD models to obtain the atom-in-molecules volumes used by...
Preprint
Full-text available
GC-rich sequences are recurring motifs in oncogenes and retroviruses, and could be targeted by non-covalent major-groove therapeutic ligands. We considered the palindromic sequence d(G1G2C3G4C5C6)2, and designed several oligopeptide derivatives of the anti-cancer intercalator mitoxantrone. The stability of their complexes with a 18-mer oligonucleot...
Article
Full-text available
We report a fast-track computationally-driven discovery of new SARS-CoV2 Main Protease Mpro inhibitors whose potency range from mM for initial non-covalent ligands to sub-μM for the final covalent compound (IC50=830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energy c...
Preprint
Full-text available
We propose a new strategy to solve the Many-Body Dispersion (MBD) model by Tkatchenko, DiStasio Jr. and Ambrosetti. Our approach overcomes the original O(N**3) computational complexity that limits its applicability to large molecular systems within the context of O(N) Density Functional Theory (DFT). First, in order to generate the required frequen...
Preprint
Full-text available
We present the extension of the SIBFA (Sum of Interactions Between Fragments Ab initio Computed) many-body polarizable force field to condensed phase Molecular Dynamics (MD) simulations. The Quantum-Inspired SIBFA procedure is grounded on simplified integrals obtained from localized molecular orbital theory and achieves full separability of its int...
Preprint
Full-text available
We propose a new strategy to solve the Tkatchenko-Scheffler Many-Body Dispersion (MBD) model's equations. Our approach overcomes the original O(N 3) computational complexity that limits its applicability to large molecular systems within the context of O(N) Density Functional Theory (DFT). First, in order to generate the required frequency-dependen...
Preprint
Full-text available
We propose a new strategy to solve the Tkatchenko-Scheffler Many-Body Dispersion (MBD) model’s equations. Our approach overcomes the original O(N**3) computational complexity that limits its applicability to large molecular systems within thecontext of O(N) Density Functional Theory (DFT). First, in order to generate the required frequency-dependen...
Preprint
Full-text available
We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field.By adding harmonic...
Preprint
We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field.By adding harmonic...
Preprint
Full-text available
We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmo...
Preprint
We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmo...
Preprint
Full-text available
We report a fast-track computationally-driven discovery of new SARS-CoV2 Main Protease (Mpro) inhibitors whose potency range from mM for initial non-covalent ligands to high nM for the final covalent compound (IC50=830 ± 50 nM). The project extensively relied on high-resolution all-atom molecular dynamics simulations and absolute binding free energ...
Preprint
Full-text available
We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmo...
Preprint
We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs-accelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmo...
Preprint
Full-text available
We detail a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUsaccelerated implementation within the Tinker-HP molecular dynamics package. We then introduce the new "dual-water" mode and its use with the flexible AMOEBA polarizable force field. By adding harmon...
Preprint
We introduce a novel multi-level enhanced sampling strategy grounded on Gaussian accelerated Molecular Dynamics (GaMD). First, we propose a GaMD multi-GPUs -accelerated implementation within Tinker-HP. For the specific use with the flexible AMOEBA polarizable force field (PFF), we introduce the new "dual–water" GaMD mode. By adding harmonic boosts...
Article
Following our previous work (Chem. Sci. 2021, 12, 4889−4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 μs) 10 using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bond network...
Article
Full-text available
The computational modeling of realistic extended systems, relevant in, e.g., Chemistry and Biophysics, is a fundamental problem of paramount importance in contemporary research. Enzymatic catalysis and photoinduced processes in pigment–protein complexes are typical problems targeted by computer-aided approaches, to complement experiments as interpr...
Preprint
Full-text available
Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bo...
Preprint
Following our previous work (Chem. Sci., 2021, 12, 4889 – 4907), we study the structural dynamics of the SARS-CoV-2 Main Protease dimerization interface (apo dimer) by means of microsecond adaptive sampling molecular dynamics simulations (50 microseconds) using the AMOEBA polarizable force field (PFF). This interface is structured by a complex H-bo...
Article
Computational protein design, ab initio protein/RNA folding, and protein–ligand screening can be too computationally demanding for explicit treatment of solvent. For these applications, implicit solvent offers a compelling alternative, which we describe here for the polarizable atomic multipole AMOEBA force field based on three treatments of contin...
Article
Full-text available
We present the extension of the Tinker-HP package (Lagard\`ere et al., Chem. Sci., 2018,9, 956-972) to the use of Graphics Processing Unit (GPU) cards to accelerate molecular dynamics simulations using polarizable many-body force fields. The new high-performance module allows for an efficient use of single- and multi-GPU architectures ranging from...
Article
Full-text available
We provide an unsupervised adaptive sampling strategy capable of producing μs-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFF). The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within a selective process to achieve sufficient pha...
Preprint
Full-text available
We demonstrate the accuracy and efficiency of a recently introduced approach to account for nuclear quantum effects (NQE) in molecular simulations: the adaptive Quantum Thermal Bath (adQTB). In this method, zero point energy is introduced through a generalized Langevin thermostat designed to precisely enforce the quantum fluctuation-dissipation the...
Preprint
Computational protein design, ab initio protein/RNA folding, and protein-ligand screening can be too computationally demanding for explicit treatment of solvent. For these applications, implicit solvent offers a compelling alternative, which we describe here for the polarizable atomic multipole AMOEBA force field based on three treatments of contin...
Preprint
Full-text available
We present the extension of the Tinker-HP package (Lagardère et al., Chem. Sci., 2018,9, 956-972) to the use of Graphics Processing Unit (GPU) cards to accelerate molecular dynamics simulations using polarizable many-body force fields. The new high-performance module allows for an efficient use of single-and multi-GPUs archi-1 arXiv:2011.01207v1 [p...
Preprint
Full-text available
We provide a new unsupervised adaptive sampling strategy capable of producing microsecondtimescale molecular dynamics (MD) simulations using many-body polarizable force fields (PFF) on modern supercomputers. The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within an iterative/selective proces...
Preprint
Full-text available
We provide an unsupervised adaptive sampling strategy capable of producing microseconds-timescale molecular dynamics (MD) simulations of large biosystems using many-body polarizable force fields (PFF). The global exploration problem is decomposed into a set of separate MD trajectories that can be restarted within a selective process to achieve suff...
Article
Full-text available
We propose a new route to accelerate molecular dynamics through the use of velocity jump processes allowing for an adaptive timestep specific to each atom–atom pair (two-body) interactions. We start by introducing the formalism of the new velocity jump molecular dynamics, ergodic with respect to the canonical measure. We then introduce the new BOUN...
Article
Using polarizable (AMOEBA) and non-polarizable (CHARMM) force fields, we compare the relative free energy stability of two extreme conformations of the HIV-1 NCp7 nucleocapsid that had been previously experimentally advocated to prevail in solution. Using accelerated sampling techniques, we show that they differ in stability by no more than 0.75-1....
Preprint
Full-text available
We propose a new route to accelerate molecular dynamics through the use of velocity jump processes allowing for an adaptive time-step specific to each atom-atom pair (2-body) interactions. We start by introducing the formalism of the new velocity jump molecular dynamics, ergodic with respect to the canonical measure. We then introduce the new BOUNC...
Preprint
The Human Immunodeficiency Virus Type 1 nucleocapsid 7 (NCp7) is a multi-functional protein formed by N-terminal and C-terminal domains surrounding two Zn-fingers, linked by a stretch of basic residues, which play a key role in the viral replica-tion. We report the first NCp7 polarizable molecular dynamics (MD) study using the AMOEBA force field co...
Preprint
The Human Immunodeficiency Virus Type 1 nucleocapsid 7 (NCp7) is a multi-functional protein formed by N-terminal and C-terminal domains surrounding two Zn-fingers, linked by a stretch of basic residues, which play a key role in the viral replica-tion. We report the first NCp7 polarizable molecular dynamics (MD) study using the AMOEBA force field co...
Article
Full-text available
This living paper reviews the present High Performance Computing (HPC) capabilities of the Tinker-HP molecular modeling package. We focus here on the reference, double precision, massively parallel molecular dynamics engine present in Tinker-HP and dedicated to perform large scale simulations. We show how it can be adapted to recent Intel Central P...
Article
We extend the framework for polarizable force fields to include the case where the electrostatic multipoles are not determined by a variational minimization of the electrostatic energy. Such models formally require that the polarization response is calculated for all electrostatic variables for all possible geometrical perturbations in order to obt...
Preprint
Full-text available
This living paper reviews the present High Performance Computing (HPC) capabilities of the Tinker-HP molecular modeling package. We focus here on the reference, double precision, massively parallel molecular dynamics engine present in Tinker-HP and dedicated to perform large scale simulations. We show how it can be adapted to recent Intel Central P...
Preprint
Full-text available
We extend the framework for polarizable force fields to include the case where the electrostatic multipoles are not determined by a variational minimization of the electrostatic energy. Such models formally require that the polarization response is calculated for all electrostatic parameters for all possible geometrical perturbations in order to ob...
Preprint
div>We extend the framework for polarizable force fields to include the case where the electrostatic multipoles are not determined by a variational minimization of the electrostatic energy. Such models formally require that the polarization response is calculated for all electrostatic parameters for all possible geometrical perturbations in order...
Article
Full-text available
In this work, we present a general route to hybrid quantum mechanics/molecular mechanics dynamics for complex systems using a polarizable embedding. We extend the capabilities of our hybrid framework, combining the Gaussian and Tinker/Tinker-HP packages in the context of the polarizable force field AMOEBA to treat large (bio)systems where the QM an...
Article
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Steered Molecular Dynamic (SMD) is a powerful technique able to accelerate rare events sampling in Molecular Dynamics (MD) simulations by applying an external force to a set of chosen atoms. Despite generating non-equilibrium simulations, SMD remains capable of reconstructing equilibrium properties such as the Potential of Mean Force (PMF). Of cour...
Article
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We propose an incremental construction of multi-timestep integrators to accelerate polarizable point dipole molecular dynamics while preserving sampling efficiency. We start by building various integrators using frequency-driven splittings of energy terms and a Velocity-Verlet evaluation of the most rapidly varying forces, and compare a standard du...
Preprint
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This paper is dedicated to the massively parallel implementation of Steered Molecular Dynamics in the Tinker-HP softwtare. It allows for direct comparisons of polarizable and non-polarizable simulations of realistic systems.
Article
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We illustrate the domain decomposition Conductor-like Screening Model (ddCOSMO) implementation and how to couple it with an existing classical or quantum mechanical (QM) code. We review in detail what input needs to be provided to ddCOSMO and how to assemble it, describe how the ddCOSMO equations are solved and how to process the results in order t...