Acellera's Blog

Complete protein–protein kinetics by molecular dynamics

From Stefan Doerr

Proteins are essential in the regulation of most of the processes in a cell. They do so by interacting with other molecules, including other proteins.
Protein-protein interactions have been the subject of study for a long time using both experimental and computational methods, however they have eluded the atomic-level analysis and accuracy that unbiased molecular dynamics simulations can provide.

Franck ChevalierComplete protein–protein kinetics by molecular dynamics
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A Decade of GPUs based MD

By Gerard Martinez-Rosell

ACEMD was introduced in the field of Molecular Dynamics (MD) back in 2008. Its release, together with other MD engines, revolutionized the simulation throughput by leveraging the intrinsic parallelism present in a specific computer processor termed GPU (Graphic Processor Unit). Using a cluster of GPUs or a distributed network like GPUGRID one is able to reach performances of HPC-class computers using commodity software, yielding a significant (x10) reduction in the Euro/simulated time cost. Furthermore, the evolution of GPUs performance, which is mainly driven by a market demanding more graphic processing power (e.g. in videogames), has doubled approximately every 3 years and with it, since 2008, ACEMD performance has increased 2.1x. To illustrate this fact, we have compiled the maximum simulated time per year published by prof. Gianni de Fabritiis using ACEMD (which yields the oldest historic data) and we extrapolate that the MD field will reach the second aggregated time timescale by 2022.

Franck ChevalierA Decade of GPUs based MD
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Helical unwinding and side-chain unlocking unravel the outward open conformation of the melibiose transporter

By Alex Perálvarez-Marín


In Wang et al. we have studied and described an intermediate step of the molecular mechanism of sugar transport thanks to the possibility to run several MD simulation replicates in the 100 ns range using a single GPU-based desktop running ACEMD. Our solvated membrane protein system embedded in the lipid bilayer consisted of ca. 100,000 atoms, and the combination between ACEMD and a single GTX-780 helped us to understand discrete events happening between two metastable intermediates. The combination of MD simulations and experimental data was key to achieve our goal to understand the conformational changes to allow the entrance of the substrates within the transporter. For the full story, refer to Wang et al Sci Rep 2016(

For the full story, refer to Wang et al Sci Rep 2016(

Franck ChevalierHelical unwinding and side-chain unlocking unravel the outward open conformation of the melibiose transporter
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Acellera, celebrating the 10th Anniversary

What has been achieved in Molecular Dynamics and Acellera contribution.

Acellera celebrates its 10th anniversary. A decade focusing on molecular dynamics (MD) and dedicated to improve this technique as a strong partner of biophysical approaches. Objectively, molecular dynamics is the only technique allowing to study conformational changes and interaction at atomistic level, to quantify binding energies, binding kinetics for any kind of molecules since a force field has been defined for these. It represents an adequate combination with NMR, Crystallography, ITC, Surface plasmon resonance, Thermal shift that are already widely used in Drug Discovery.

Franck ChevalierAcellera, celebrating the 10th Anniversary
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By Franck Chevalier

Introduction on kinetics

Quest for new drug discovery usually involves a clear understanding of ligand binding to its receptor. Free binding energy helps to rank compounds and allows to select those based on their target affinity. Drug discovery programs focused on optimization of target affinity as a proxy of in-vivo efficacy. Within the last years, researchers have increasingly become interested in measuring and understanding drugs’ binding kinetics. Namely, the time in which drug and its target associate and dissociate.

Until recently, few methods offered the possibility to determine kinetics parameters and almost none at atomistic resolution. Amazing recent emergence of computational methods provided powerful tools in measuring and understanding binding event. It offers interesting and accurate methods to determine qualitative (binding mode) and quantitative (binding energy, Kon, Koff) parameters in a single atomistic approach.

Determination of these parameters with HTMD has been reviewed in previous posts:
such as this one . Recent works that highlight the importance of binding, molecular recognition and molecular determinants for rational optimization have been reviewed here.

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Acellera, Spring & Summer’16 conferences

By Franck Chevalier

Meet Acellera during Spring & Summer’16 Conferences.

Fragment Based Drug Discovery (FBDD), Markov state model, free energy methods, drug discovery by high throughput molecular dynamics (HTMD); these are few of the topics developed during the events we will join within the next weeks.

Franck ChevalierAcellera, Spring & Summer’16 conferences
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GPCR Unbiased lipid-like ligand binding with ACEMD

By Franck Chevalier


The binding process through the membrane bilayer of lipid-like ligands to a GPCR protein target is an important but poorly explored recognition process at the atomic level. In this work ,the binding of the lipid inhibitor ML056 to the sphingosine-1-phosphate receptor 1 (S1P1R) has been successfully reported using unbiased molecular dynamics simulations with an aggregate sampling of over 800 μs. The binding pathway is a multi-stage process consisting of the ligand diffusing in the bilayer leaflet to contact a “membrane vestibule” at the top of TM 7, subsequently moving from this lipid-facing vestibule to the orthosteric binding cavity through a channel formed by TMs 1 and 7 and the N-terminal of the receptor. Unfolding of the GPCR N-terminal alpha-helix increases the volume of the channel upon ligand entry, helping to reach the crystallographic pose that also corresponds to the predicted favorable pose. The relaxation timescales of the binding process show that the binding of the ligand to the “membrane vestibule” is the rate-limiting step in the multi microseconds timescale. We comment on the significance and parallels of the binding process in the context of other binding studies.

Current challenges

Both ACEMD and HTMD software have permitted to perform the preparation, simulation and analysis of trajectories and elucidate the binding pathway along with critical atomic interactions and conformational changes. Similar to other studies of ligand binding to GPCRs4 , there is a barrier to binding that occurs far away from the final binding pose. This barrier is formed by the interaction between the zwitterionic head group of the ligand and R2927.34 and E2947.36 in the “membrane vestibule” and the desolvation necessary for the ligand to enter the channel.

A final barrier is due to rearrangements of the water molecules in the binding cavity and of dihedral angles in the head and tail of the ligand such that all these favorable interactions can be formed.

Along the binding process, the widening of the cavity by the flexible N-terminus and the desolvation of the ligand head group appear as general trends.



In this work,  the binding of a lipid-like ligand from the membrane bilayer directly to the orthosteric binding site of a GPCR using unbiased MD simulations has been shown. The ML056 inhibitor, studied here, binds S1P1R through a multi-step process that finally leads to the crystallographic binding pose.



Nathaniel Stanley, Leonardo Pardo & Gianni De Fabritiis, The pathway of ligand entry from the membrane bilayer to a lipid G protein-coupled receptor (GPCR), Scientific Reports 2016

Franck ChevalierGPCR Unbiased lipid-like ligand binding with ACEMD
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Fragment Hit Binding by Molecular Simulations

By Franck Chevalier



During the last 20 years, a great interest has been shown for fragment in order to answer one of the major issue faced by traditional drug discovery program: by its properties, it allows to reduce the number of molecules tested whatever the method used, series are directly related to fragment and optimization of hit is more intuitive. Fragment based drug discovery (FBDD) by molecular dynamics offers now an awesome tool for fragment hit binding.

How has FBDD evolved?

A brief analysis of articles published within last two decades shows that main techniques used include bioassay (inhibition assay, radiolabeled binding assay…) and biophysical methods (Crystallography, NMR, SPR, MS, ITC…).

Low affinity showed by most fragment for their target limits the range of detection for most methods and are not necessarily the high affinity binder that are detected. Most articles in FBDD present the use of a single method, mainly in vitro bioassay. The rate of new articles is about 150/year. Expertise needed, throughput and cost of main biophysics methods still limit their access.

Which alternative?

Within the same period, we observed an increase of publications on virtual methods. Molecular dynamics simulations have been published in more than tens of thousands articles. Interestingly less than 5% of these publications deal about discovery at a yield of 300 publications/year within the last few years.

When FBDD is performed, about 1 to 2 techniques are used. If more than 2 techniques are used, 50% of publications mention the use of virtual methods. About 30% only used virtual methods and tendency has been increased. The large dataset of structures generated by crystallography empowered the use of docking. The important role played by protein flexibility has been answered with molecular dynamics.

Discovery or design?

At this stage, most work focused on discovery, meaning the detection of molecules able to bind, inhibit or activate the target. Few articles yet deals about linking, merging, growing fragment.

Targeting what?

Favorite targets are kinase, enzymes but more complex system involving ion channel, GPCR are now reported.

Reliability of molecular dynamics

In silico FBDD’s impact on lead development has been limited to date. Inability to describe kinetics and conformational changes upon binding are some of the reasons. In the following reference, a comprehensive computational assay for fragment hit characterization has been performed: 2.1 ms of unbiased all-atom high-throughput molecular dynamics (HTMD) data were obtained and analyzed to show the potential of this technique for FBDD.


Reference: Noelia Ferruz,Matthew J. Harvey,  Jordi Mestres, and Gianni De Fabritiis J. Chem. Inf. Model. 2015, 55, 2200−2205

Franck ChevalierFragment Hit Binding by Molecular Simulations
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HTMD: Molecular discovery simplified

By Stefan Doerr


Molecular dynamics simulations (MD) can provide an atomic level resolution of biological processes at very high temporal resolution, but it comes with its own set of limitations; the most pronounced ones being the accuracy of the forcefields and the time sampling limitations.

Yet, we believe that there are further important problems: the data analysis and the reproducibility of experiments. In the last few years, specialized hardware, high-throughput methods and advanced sampling techniques have come to significantly improve molecular dynamics, allowing them to reach aggregate simulation times of multiple milliseconds. Forcefields have also dramatically improved. This increase of simulation accuracy and data has led to the necessity of a more standardized methodology for preparing, executing and handling thousands of individual trajectories.

Recently we have been working on provide an environment for molecular discovery which simplifies every step of molecular modelling and simulations. We call this environment high-throughput molecular dynamics (HTMD) and the final paper is now published in JCTC. A short intro is provided in this blog.


Current challenges

Investigating biological processes using MD usually requires the processing of large amounts of data and files, using various tools and adapting to peculiarities of many different software packages developed over several decades. With all these fragile set of tools, it is hard to follow the steps of a workflow that lead from the original PDB to the results, even for the scientist who wrote the workflow. Secondly, it is hard to extend the functionality of the tools because of such diversity of languages and the absence of a common programming environment where to introduce new extensions.

Our vision

HTMD is our vision of a unified platform, a programmable workspace for simulation based molecular discovery. We name it HTMD (high-throughput molecular dynamics) to indicate the fact that it allows the handling of thousands of simulations and multiple systems in a controlled manner. HTMD extends the Python programming language with functions and classes to handle molecular systems at different levels while abstracting implementation details and best-practice knowledge. Python is a scripting language which enjoys widespread usage in the scientific community and thus provides an ideal platform on which to develop and distribute HTMD. HTMD’s functionalities span from molecular structure manipulation to visualization, to preparing and executing molecular simulations on different compute resources and data analysis, including the use of Markov state models (MSMs) to identify slow events, kinetic rates, affinities and pathways.


Stefan Doerr, Matthew J. Harvey, Frank Noé, and Gianni De Fabritiis, HTMD: High-throughput molecular dynamics for molecular discovery, in press JCTC 2016

Franck ChevalierHTMD: Molecular discovery simplified
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