Biology subjects

Bereau, T.

Publications and source records attributed to Bereau, T..

7 recordsLinked to original sources

bioRxiv2025

Fast parameterization of Martini3 models for fragments and small molecules

Coarse-grained molecular dynamics simulations, such as those performed with the recently parametrized Martini 3 force field, simplify molecular models and enable the study of larger systems over longer timescales. With this new implementation, Martini 3 allows more bead types and sizes, becoming more amenable to study dynamical phenomena involving small molecules such as protein-ligand interactions and membrane permeation. However, while there were some solutions to automatically model small molecules using the previous iteration of Martini force field, there is no simple way to generate such molecules for Martini 3 yet. Here, we introduce Auto-MartiniM3, an advanced and updated version of the Auto-Martini program, designed to automate the coarse-graining of small molecules to be used with the Martini 3 force field. We validated our approach by modeling 81 small molecules from the Martini Database and comparing their structural and thermodynamic properties with ones obtained from models designed by Martini experts. Additionally, we assessed the behavior of Auto-MartiniM3-generated models by calculating solute translocation and free energy across lipid bilayers. We also evaluated more complex molecules such as caffeine by testing its binding to the adenosine A2A receptor. Finally, our results from deploying Auto-MartiniM3 on a large dataset of molecular fragments demonstrate that this program can become a tool of choice for fast high-throughput creation of coarse-grained models of small molecules, offering a good balance between automation and accuracy. Auto-MartiniM3 source code is freely available at https://github.com/Martini-Force-Field-Initiative/Automartini_M3

bioinformatics↗

bioRxiv2020

Finite-size transitions in complex membranes

The lipid raft hypothesis postulates that cell membranes possess some degree of lateral organization. The last decade has seen a large amount of experimental evidence for rafts. Yet, the underlying mechanism remains elusive. One hypothesis that supports rafts relies on the membrane to lie near a critical point. While supported by experimental evidence, the role of regulation is unclear. Using both a lattice model and molecular dynamics simulations, we show that lipid regulation of a many-component membrane can lead to critical behavior over a large temperature range. Across this range, the membrane displays a critical composition due to finite-size effects. This mechanism provides a rationale as to how cells tune their composition without the need for specific sensing mechanisms. It is robust and reproduces important experimentally verified biological trends: membrane-demixing temperature closely follows cell growth temperature, and the composition evolves along a critical manifold. The simplicity of the mechanism provides a strong argument in favor of the critical membrane hypothesis. SIGNIFICANCEWe show that biological regulation of a large amount of phospholipids in membranes naturally leads to a critical composition for finite-size systems. This suggests that regulating a system near a critical point is trivial for cells. These effects vanish logarithmically and therefore can be present in micron-sized systems.

biophysics↗

bioRxiv2020

Moleculewise semi-grand canonical ensembles

The plasma membrane is the interface between cells and exterior media. While its existence has been known for a long time, organization of its constituent lipids remain a challenge. Recently, we have proposed that lipid populations may be controlled by chemical potentials of different lipid species, resulting in semi-grand canonical thermodynamic ensembles. However, the currently available molecular dynamics software packages do not allow for molecule-based chemical potentials. Here, we propose a variation on existing algorithms that allow defining chemical potentials for molecules. Additionally, we allow coupling with collective variables and show that it can be used to dynamically create asymmetric membranes. We release an implementation of the algorithm for the HOOMD-Blue molecular dynamics engine. SIGNIFICANCEWe demonstrate an algorithm that allows for simulations of molecules in the semi-grand canonical ensemble. It also allows coupling the chemical potential values to collective variable and create asymmetric membranes.

biophysics↗

bioRxiv2019

Regulating lipid composition rationalizes acyl-tail saturation homeostasis in ectotherms

Cell membranes mainly consist of lipid bilayers with an actively regulated composition. The underlying processes are still poorly understood, in particular how the hundreds of components are controlled. Surprisingly, in recent experiments on ectotherms, the cholesterol fraction, along with un- and mono-saturated acyl tail fractions and demixing temperatures, was shown to increase with body temperature. We establish a model based on chemical reaction networks to study regulation of membranes, resulting in multiple semi-grand canonical ensembles. By running computer simulations, we show that higher cholesterol fractions correlate with lower degrees of unsaturation, ultimately controlling the composition of lipid tails. Cholesterol also dictates membrane viscosity and regulation of the latter implies that cholesterol must increase with temperature. Overall, our model proposes a different picture of lipid regulation, where components can be passively, instead of actively, regulated. SIGNIFICANCEIn this article, we propose a regulation model where only some of the components are actively regulated between membranes, while others are naturally balanced by chemical potentials. This model provides a rationale to recently measured puzzling trends in ectotherms, that is, increased plasma membrane cholesterol fraction with temperature. Here, we show that it is directly correlated with with acyl tail saturation and order parameter correlation length. Furthermore, we highlight the relation between cholesterol and membrane viscosity.

biophysics↗

bioRxiv2019

Inserting small molecules across membrane mixtures: Insight from the potential of mean force

Small solutes have been shown to alter the lateral organization of cell membranes and reconstituted phospholipid bilayers; however, the mechanisms by which these changes happen are still largely unknown. Traditionally, both experiment and simulation studies have been restricted to testing only a few compounds at a time, failing to identify general molecular descriptors or chemical properties that would allow extrapolating beyond the subset of considered solutes. In this work, we probe the competing energetics of inserting a solute in different membrane environments by means of the potential of mean force. We show that these calculations can be used as a computationally-efficient proxy to establish whether a solute will stabilize or destabilize domain phase separation. Combined with umbrella sampling simulations and coarse-grained molecular dynamics simulations, we are able to screen solutes across a wide range of chemistries and polarities. Our results indicate that, for the system under consideration, preferential partitioning and therefore effectiveness in altering membrane phase separation are strictly linked to the location of insertion in the bilayer (i.e., midplane or interface). Our approach represents a fast and simple tool for obtaining structural and thermodynamic insight into the partitioning of small molecules between lipid domains and its relation to phase separation, ultimately providing a platform for identifying the key determinants of this process.\n\nSIGNIFICANCEIn this work we explore the relationship between solute chemistry and the thermodynamics of insertion in a mixed lipid membrane. By combining a coarse-grained resolution and umbrella-sampling simulations we efficiently sample conformational space to study the thermodynamics of phase separation. We demonstrate that measures of the potential of mean force--a computationally-efficient quantity--between different lipid environments can serve as a proxy to predict a compounds ability to alter the thermodynamics of the lipid membrane. This efficiency allows us to set up a computational screening across many compound chemistries, thereby gaining insight beyond the study of a single or a handful of compounds.

biophysics↗

bioRxiv2017

The role of conformational entropy in the determination of structural-kinetic relationships for helix-coil transitions

Coarse-grained molecular simulation models can provide significant insight into the complex behavior of protein systems, but suffer from an inherently distorted description of dynamical properties. We recently demonstrated that, for a heptapeptide of alanine residues, the structural and kinetic properties of a simulation model are linked in a rather simple way, given a certain level of physics present in the model. In this work, we extend these findings to a longer peptide, for which the representation of configuration space in terms of a full enumeration of sequences of helical/coil states along the peptide backbone is impractical. We verify the structural-kinetic relationships by scanning the parameter space of a simple native-biased model and then employ a distinct transferable model to validate and generalize the conclusions. Our results further demonstrate the validity of the previous findings, while clarifying the role of conformational entropy in the determination of the structural-kinetic relationships. More specifically, while the global, long timescale kinetic properties of a particular class of models with varying energetic parameters but approximately fixed conformational entropy are determined by the overarching structural features of the ensemble, a shift in these kinetic observables occurs for models with a distinct representation of steric interactions. At the same time, the relationship between structure and more local, faster kinetic properties is not affected by varying the conformational entropy of the model.

biophysics↗

bioRxiv2017

Structure-kinetic-thermodynamic relationships for peptide secondary structure formation identified from transition network properties

Coarse-grained molecular simulation models have provided immense, often general, insight into the complex behavior of condensed-phase systems, but suffer from a lost connection to the true dynamical properties of the underlying system. In general, the physics that is built into a model shapes the free-energy landscape, restricting the attainable static and kinetic properties. In this work, we perform a detailed investigation into the property interrelationships resulting from these restrictions, for a representative system of the helix-coil transition. Inspired by high-throughput studies, we systematically vary force-field parameters and monitor their structural, kinetic, and thermodynamic properties. The focus of our investigation is a simple coarse-grained model, which accurately represents the underlying structural ensemble, i.e., effectively avoids sterically-forbidden configurations. As a result of this built-in physics, we observe a rather large restriction in the topology of the networks characterizing the simulation kinetics. When screening across force-field parameters, we find that structurally-accurate models also best reproduce the kinetics, suggesting structural-kinetic relationships for these models. Additionally, an investigation into thermodynamic properties reveals a link between the cooperativity of the transition and the network topology at a single reference temperature.

biophysics↗