Research lines
Our research focuses on mesoscopic computational modeling and simulations mainly of biological systems. We attempt to solve new scientific problems by developing new methodologies, software and ideas for bridging between the atomistic scale (femtoseconds, nanometers) and the biological molecular scale (micro- to milli-seconds and hundreds of nanometers).
Research lines:
Equilibrium energetics of molecular systems and protein interactions. Calculations of energetics for molecular systems is of great importance for understanding and controlling protein functions. We apply several techniques for free energy calculations to the understanding of molecular mechanisms like ion permeation, ion binding, ligand binding and protein aggregation. In particular, we are interested to in-silico high-throughput approaches but maintaining thermodynamic accuracy. For this, we are using our GPUGRID.net infrastructure.
Non-equilibrium macromolecular dynamics. Building on our previous research for molecular-hydrodynamics interactions, we are looking at resonance patterns of proteins embedded in a hydrodynamics solvent description and how external sound waves can perturb their equilibrium state.
Accelerated and distributed molecular simulation methods. In order to support our research we developed innovate software solutions (ACEMD,http://multiscalelab.org/acemd) for molecular dynamics on accelerator processors (Cell and GPUs), as well as one of the largest distributed computing project worldwide, GPUGRID.net (http://gpugrid.net). This gives us the computational power to tackle problems substantially beyond the state of the art. In fact, whilst the fundamental thermodynamic framework behind the simulation of macromolecules is well characterized, exploration of biological time scales remains beyond the computational capacity routinely available to many researchers. With ACEMD and GPUGRID our group can be considered at the fore front of computational biophysics and biochemistry.
Research gallery
Funding acknowledgments
- Sony Computer Entertainment Spain
- Nvidia Corporation
- Ramon y Cajal grants
- EU research program (Virtual Physiological human)
- National research plan
ACEMD: Accelerated molecular dynamics simulations in the microseconds timescale
The high arithmetic performance and intrinsic parallelism of recent graphical processing units (GPUs) can offer a technological edge for molecular dynamics simulations. ACEMD is a production-class bio-molecular dynamics (MD) simulation program designed specifically for GPUs which is able to achieve supercomputing scale performance of 40 nanoseconds/day for all-atom protein systems with over 23,000 atoms. We illustrate the characteristics of the code, its validation and performance. We also run a microsecond-long trajectory for an all-atom molecular system in explicit TIP3P water on a single workstation computer equipped with just 3 GPUs. This performance on cost effective hardware allows ACEMD to reach microsecond timescales routinely with important implications in terms of scientific applications. M. Harvey, G. Giupponi and G. De Fabritiis, ACEMD: Accelerated molecular dynamics simulations in the microseconds timescale, preprint (2009).
Performance of the Cell processor for biomolecular simulations
The Cell broadband engine is a new processor architecture created by Sony-Toshiba-IBM\cite{ibmcellsite} which allows for high computational performance and low production costs removing, by design, many important bottlenecks of standard processors. In the present version, it comprises one simplified power PC core (PPE) which runs the operating system and acts as a standard processor and 8 independent synergetic processing elements (SPEs). Main memory can be accessed only by the PPE core while each SPE can use its limited in-chip local memory (local store) accessed directly without any intermediate caching. This architectural design removes the memory bottleneck which is afflicting modern processors and furnishes a direct way to improve performance by adding more SPEs without having to rely only on clock frequency. Each core (PPE or SPEs) features a single instruction multiple data (SIMD) vector unit which gives a combined peak performance of around 230 Gflops at 3.2Ghz. I have looked at the important application case of molecular dynamics. G. De Fabritiis, Performance of the Cell processor for biomolecular simulations, Comp. Phys. Commun. 176, 670 (2007).pdf
Hybrid molecular dynamics (MD) - fluctuating hydrodynamics (FH)
Hybrid MD is a multiphysics (multiscale) coupled model between molecular dynamics (MD) and a continuum representation of a mesoscale fluid resolved by fluctuating hydrodynamics (FH). This very power technique allow simulation of large time and length scales keeping the molecular specificy in a sub-domain of the entire system (for instance a boundary condition). The two models MD and FH are separate executables which can be deploied on different computational resources but interface on-the-fly by exchanging momentum and mass. The coupling protocol requires to mantain a open MD system which is made possible by new algorithms of molecule insertion. G. De Fabritiis, R. Delgado-Buscalioni and P. V. Coveney, Modelling the mesoscale with molecular specificity, Phys. Rev. Lett. 97, 134501 (2006). pdf
Energetics of K+ permeability through Gramicidin A by forward-reverse steered molecular dynamics
The permeation of ions in protein channels is important to control cell activity. However, a direct measurement of the conductivity via molecular simulations is not possible because the time scales involved are too long (micro-milli seconds). Rather, the potential of mean force (PMF) of the crossing is computed and the conductance estimated from it. We are currently looking at a simple non-equilibrium method to compute the PMF which is based on the Crooks non-equilibrium relation [Phys. Rev. E 61 2361 (2000)] over the Gramicidin A membrane protein. The equilibrium PMF is reconstructed from a set of controlled non-equilibrium pullings of ions trough the channel. This procedure also allows to compute the position dependent diffusion coefficient. G. De Fabritiis, P. V. Coveney and J. Villa-Freixa, Energetics of K+ permeability through Gramicidin A by forward-reverse steered molecular dynamics, 73, 184 Proteins (2008).pdf
Insights from the energetics of water binding at the domain ligand interface of the Src SH2 domain
SH2 domains play important roles in signal transduction by binding phosphorylated tyrosine residues on cell surface receptors. In an effort to understand the mechanism of ligand binding and more specifically the role of water, we have designed a general computational protocol based on the potential of mean force to compute the thermodynamics of water molecules at the protein-ligand interface for two SH2 domain complexes of the Src kinase, those bound to the two peptides Ac-PQpYEpYI-NH2 and Ac-PQpYIpYV-NH2 where pY indicates a phosphotyrosine. These two peptides were chosen because they have similar binding affinities but very different entropic/enthalpic thermodynamic binding signatures, indicating different interactions with solvent. We find that the isoleucine to valine mutation at position +3 (the third amino acid C-terminal to pY) in the ligand has only limited impact on the water structure. By contrast, the glutamic acid to isoleucine mutation at position +1 has a significant impact by not only abrogating a local hydrophilic binding site but, more importantly and surprisingly, inducing a favorable nonlocal entropic contribution from the water molecules around the phosphorylated tyrosine at the +2 position. Our study demonstrates the validity of the method reported here for exploring the thermodynamic solvation landscape of protein-protein interactions. G. De Fabritiis, S. Geroult, P. V. Coveney and G. Waksman, Insights from the energetics of water binding at the domain-ligand interface of the Src SH2 domain, 72, 1290 Proteins (2008). journal link