arXiv subjects

Jérôme Hénin

Publications and source records attributed to Jérôme Hénin.

11 recordsLinked to original sources

arXiv2026

LAO+: Focused, Multi-Replica Accelerated Orthogonal Sampling for Robust Binding Free Energy Predictions

We introduce Lambda-ABF-OPES+ ($\text{LAO+}$), a multi-replica framework for absolute binding free energy (ABFE) calculations that accelerates both the alchemical transformation and the slow ``orthogonal'' motions coupled to it. At the core of $\text{LAO+}$ is a partitioned $λ$-dynamics scheme that concentrates sampling on the abrupt rehydration of the binding pocket, the main bottleneck of ligand decoupling, while Hamiltonian replica exchange relays configurations along the entire alchemical path. This drives a fourfold gain in convergence speed for the rate-limiting leg over our previous $\text{LAO}$ method, which was itself up to ninefold faster than Lambda-ABF, an overall gain of up to $\sim$36-fold. Applied to 28 protein--ligand complexes across five targets, $\text{LAO+}$ achieves a root-mean-square error of 0.83~kcal~mol$^{-1}$ and a correlation of 0.87 with experiment from only 63~ns of sampling per ligand. Moreover, dedicated reservoir replicas accelerate any slow degree of freedom that can be described by a collective variable. We demonstrate this by recovering hidden protein and ligand conformational states, for example in T4 lysozyme, BRD4 and JNK1. Together, these advances make accurate ABFE calculations practical for drug discovery.

physics.comp-ph↗

arXiv2026

Dual-LAO for calculating fast and robust relative binding free energies of simple and complex transformations

Relative Binding Free Energy (RBFE) calculations are a cornerstone of rational hit-to-lead and lead optimization in modern drug discovery. However, the high computational cost and limited reliability in tackling large or complex molecular transformations often prevent their routine, high-throughput use. Here we introduce dual-LAO, a novel, highly efficient method for calculating RBFE. Building on the Lambda-ABF-OPES framework, this method combines a dual-topology setup and suitable restraints to dramatically accelerate free energy convergence. We demonstrate that dual-LAO, in combination with the AMOEBA polarizable force field, achieves an unprecedented acceleration factor of 15 to 30 times compared to current state-of-the-art methods on standard drug targets. Crucially, the approach maintains high accuracy and successfully tackles previously prohibitive molecular changes, including scaffold-hopping, buried water displacement, charge changes, ring-opening, and binding pose perturbations. This significant leap in efficiency allows for the widespread, routine integration of predictive molecular simulations into the rapid optimization cycles of drug discovery, enabling chemists to confidently model historically challenging systems in timescales compatible with real-world project deadlines.

physics.chem-ph↗

arXiv2026

Molecular signatures of pressure-induced phase transitions in a lipid bilayer

Understanding how lipid bilayers respond to pressure is essential for interpreting the coupling between membrane proteins and their native environments. Here, we use all-atom molecular dynamics to examine the pressure-temperature behavior of model membranes composed of DMPC or $Δ$9-cis-PC. Within the studied range (288-308 K, 1-2000 bar), DMPC undergoes a liquid--gel transition, while $Δ$9-cis-PC remains fluid due to unsaturation. The CHARMM36 force field reproduces experimental boundaries with high fidelity: simulated DMPC transitions deviate by only 5-10 K and 100-300 bar, and $Δ$9-cis-PC exhibits no transition. Hysteresis is modest but most pronounced when starting from low-temperature gels. We identify area per lipid, bilayer thickness, and acyl-chain gauche fraction as sensitive phase markers; among these, the gauche fraction provides the most robust signature. Simulations indicate an interdigitated gel is the equilibrium structure under finite-size conditions. However, at low temperature and high pressure, interdigitation decreases, consistent with the experimental lamellar gel phase. This long-lived interdigitation critically impacts standard order parameters, specifically area per lipid and membrane thickness. These results underscore the accuracy of modern force fields and highlight how simulations mechanistically complement experimental studies of pressure-regulated membranes.

cond-mat.soft↗

arXiv2025

Lambda-ABF-OPES: Faster Convergence with High Accuracy in Alchemical Free Energy Calculations

Predicting the binding affinity between small molecules and target macromolecules while combining both speed and accuracy, is a cornerstone of modern computational drug discovery which is critical for accelerating therapeutic development. Despite recent progresses in molecular dynamics (MD) simulations, such as advanced polarizable force fields and enhanced-sampling techniques, estimating absolute binding free energies (ABFE) remains computationally challenging. To overcome these difficulties, we introduce a highly efficient, hybrid methodology that couples the Lambda-Adaptive Biasing Force (Lambda-ABF) scheme with On-the-fly Probability Enhanced Sampling (OPES). This approach achieves up to a nine-fold improvement in sampling efficiency and computational speed compared to the original Lambda-ABF when used in conjunction with the AMOEBA polarizable force field, yielding converged results at a fraction of the cost of standard techniques.

physics.chem-ph↗

arXiv2024

Lambda-ABF: Simplified, Portable, Accurate and Cost-effective Alchemical Free Energy Computations

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 $λ$-dynamics. Unbiased alchemical free energy surfaces are naturally recovered by Thermodynamic Integration (TI). No manual optimization of the $λ$ schedule is required as the sampling of the $λ$ variable is continuous and converges towards a uniform distribution. Free diffusion of $λ$ improves orthogonal relaxation compared to fixed $λ$ methods such as standard TI or Free Energy Perturbation (FEP). Furthermore, the multiple walker strategy provides coverage of orthogonal space in a generic way with minimal user input and negligible computational overhead. Of practical importance, no adiabatic decoupling between the alchemical and Cartesian degrees of freedom is assumed, ensuring unbiased estimates for a wide envelope of numerical parameters. We present two high-performance implementations of the method in production molecular dynamics engines, namely NAMD and Tinker-HP, through coupling with the Colvars open source library. These interfaces enable the combination of the rich feature sets of those packages. We demonstrate the correctness and efficiency of the approach on several real-world cases: from solvation free energies up to ligand-receptor binding (using a recently proposed binding restraint scheme) with both fixed-charge and polarizable models. We find that, for a chosen accuracy, the computational cost is strongly reduced compared to state-of-the-art fixed-lambda methods and that results within 1~kcal/mol of experimental value are recovered for the most complex system. The implementation is publicly available and readily usable by practitioners of current alchemical methods.

physics.chem-ph↗

arXiv2023

Unwrapping NPT simulations to calculate diffusion coefficients

In molecular dynamics simulations in the NPT ensemble at constant pressure, the size and shape of the periodic simulation box fluctuate with time. For particle images far from the origin, the rescaling of the box by the barostat results in unbounded position displacements. Special care is thus required when a particle trajectory is unwrapped from a projection into the central box under periodic boundary conditions to a trajectory in full three-dimensional space, e.g., for the calculation of diffusion coefficients. Here, we review and compare different schemes in use for trajectory unwrapping. We also specify the corresponding rewrapping schemes to put an unwrapped trajectory back into the central box. On this basis, we then identify a scheme for the calculation of meaningful diffusion coefficients, which is a primary application of trajectory unwrapping. In this scheme, the wrapped and unwrapped trajectory are mutually consistent and their statistical properties are preserved. We conclude with advice on best practice for the consistent unwrapping of constant-pressure simulation trajectories and the calculation of accurate translational diffusion coefficients.

physics.comp-ph↗

arXiv2023

Designing losses for data-free training of normalizing flows on Boltzmann distributions

Generating a Boltzmann distribution in high dimension has recently been achieved with Normalizing Flows, which enable fast and exact computation of the generated density, and thus unbiased estimation of expectations. However, current implementations rely on accurate training data, which typically comes from computationally expensive simulations. There is therefore a clear incentive to train models with incomplete or no data by relying solely on the target density, which can be obtained from a physical energy model (up to a constant factor). For that purpose, we analyze the properties of standard losses based on Kullback-Leibler divergences. We showcase their limitations, in particular a strong propensity for mode collapse during optimization on high-dimensional distributions. We then propose strategies to alleviate these issues, most importantly a new loss function well-grounded in theory and with suitable optimization properties. Using as a benchmark the generation of 3D molecular configurations, we show on several tasks that, for the first time, imperfect pre-trained models can be further optimized in the absence of training data.

cs.LG↗

arXiv2022

Enhanced sampling methods for molecular dynamics simulations

Enhanced sampling algorithms have emerged as powerful methods to extend the utility of molecular dynamics simulations and allow the sampling of larger portions of the configuration space of complex systems in a given amount of simulation time. This review aims to present the unifying principles and differences of many of the computational methods currenly used for enhanced sampling in molecular simulations of biomolecules, soft matter and molecular crystals. Indeed, despite the apparent abundance and divergence of such methods, the principles at their core can be boiled down to a relatively limited number of statistical and physical principles. To enable comparisons, the various methods are introduced using similar terminology and notation. We then illustrate in which ways many different methods combine principles from a smaller class of enhanced sampling concepts. This review is intended for scientists with an understanding of the basics of molecular dynamics simulations and statistical physics who want a deeper understanding of the ideas that underlie various enhanced sampling methods and the relationships between them. This living review is intended to be updated to continue to reflect the wealth of sampling methods as they continue to emerge in the literature.

cond-mat.stat-mech↗

arXiv2021

Human learning for molecular simulations: the Collective Variables Dashboard in VMD

The Collective Variables Dashboard is a software tool for real-time, seamless exploration of molecular structures and trajectories in a customizable space of collective variables. The Dashboard arises from the integration of the Collective Variables Module with the visualization software VMD, augmented with a fully discoverable graphical interface offering interactive workflows for the design and analysis of collective variables. Typical use cases include a priori design of collective variables for enhanced sampling and free energy simulations as well as post-mortem analysis of any type of simulation or collection of structures in a collective variable space. A combination of those cases commonly occurs when preliminary simulations, biased or unbiased, reveal that an optimized set of collective variables is necessary to improve sampling in further simulations. Then the Dashboard provides an efficient way to intuitively explore the space of likely collective variables, validate them on existing data, and use the resulting collective variable definitions directly in further biased simulations using the Collective Variables Module. We illustrate the use of the Dashboard on two applications: discovering coordinates to describe ligand unbinding from a protein binding site, and designing volume-based variables to bias the hydration of a transmembrane pore.

physics.comp-ph↗

arXiv2021

Fast and accurate multidimensional free energy integration

Enhanced sampling and free energy calculation algorithms of the Thermodynamic Integration family (such as the Adaptive Biasing Force method, ABF) are not based on the direct computation of a free energy surface, but rather of its gradient. Integrating the free energy surface is non-trivial in dimension higher than one. Here the author introduces a flexible, portable implementation of a Poisson equation formalism to integrate free energy surfaces from estimated gradients in dimension 2 and 3, using any combination of periodic and non-periodic (Neumann) boundary conditions. The algorithm is implemented in portable C++, and provided as a standalone tool that can be used to integrate multidimensional gradient fields estimated on a grid using any algorithm, such as Umbrella Integration as a post-treatment of Umbrella Sampling simulations. It is also included in the implementation of ABF (and its extended-system variant eABF) in the Collective Variables Module, enabling the seamless computation of multidimensional free energy surfaces within ABF and eABF simulations. A Python-based analysis toolchain is provided to easily plot and analyze multidimensional ABF simulation results, including metrics to assess their convergence. The Poisson integration algorithm can also be used to perform Helmholtz decomposition of noisy gradients estimates on the fly, resulting in an efficient implementation of the projected ABF (pABF) method proposed by Lelièvre and co-workers. In numerical tests, pABF is found to lead to faster convergence with respect to ABF in simple cases of low intrinsic dimension, but seems detrimental to convergence in a more realistic case involving degenerate coordinates and hidden barriers, due to slower exploration. This suggests that variance reduction schemes do not always yield convergence improvements when applied to enhanced sampling methods.

physics.comp-ph↗

arXiv2021

Building intuition for binding free energy calculations: bound state definition, restraints, and symmetry

The theory behind computation of absolute binding free energies using explicit-solvent molecular simulations is well-established, yet somewhat complex, with counter-intuitive aspects. This leads to frequent frustration, common misconceptions, and sometimes, erroneous numerical treatment. To improve this, we present the main practically relevant segments of the theory with constant reference to physical intuition. We pinpoint the role of the implicit or explicit definition of the bound state (or the binding site), to make a robust link between an experimental measurement and a computational result. We clarify the role of symmetry, and discuss cases where symmetry number corrections have been misinterpreted. In particular, we argue that symmetry corrections as classically presented are a source of confusion, and could be advantageously replaced by restraint free energy contributions. We establish that contrary to a common intuition, partial or missing sampling of some modes of symmetric bound states does not affect the calculated decoupling free energies. Finally, we review these questions and pitfalls in the context of a few common practical situations: binding to a symmetric receptor (equivalent binding sites), binding of a symmetric ligand (equivalent poses), and formation of a symmetric complex, in the case of homodimerization.

physics.chem-ph↗