Past Research

Assessment of force fields on small peptide conformational equilibria

In this project with Alex Tzanov at NYU, we used the driven adiabatic free energy dynamics method to efficiently sample the conformational space of small peptides whose conformational preferences have been experimentally measured, both in solution and in the gas phase. We computed the free energy surface of these peptides in the space of key dihedral angles and for which there are experimental results for

Unified free energy dynamics (UFED)

Driven adiabatic free energy dynamics (dAFED, also known as TAMD) is an efficient approach for the sampling of conformational equilibria in complex systems and the generation of associated free energy hypersurfaces in terms of a set of collective variables. The method has recently been generalized to exploit the strengths of other methods, namely using Gaussian-based adaptive bias potentials to disfavor hitherto visited regions of configuration space and using the thermodynamic force instead of the probability density to reconstruct the free energy surface. The unified free energy dynamics (UFED) scheme is shown to outperform both metadynamics and adiabatic free energy dynamics in several example cases including the alanine dipeptide and the met-enkephalin oligopeptide. In addition, UFED is not limited to one- or two-dimensional collective variables. We have showed the applicability of the method to construct free energy hypersurfaces as a function of up to 6 dihedral angles.

Both dAFED and UFED methods are implemented within an older version of the PLUMED plugin, which works with a large number of molecular dynamics software packages. The source code is available here, and the associated manual pages here.

A Matlab package to reconstruct free energy surfaces from the average force, from metadynamics-like hills, or from reweighted histograms is also available here.

Alchemical free energy differences with enhanced conformational sampling

Alchemical free energy simulations are commonly used to calculate relative binding or solvation free energies in molecular systems. The convergence of alchemical free energy calculations is often hampered by inef´Čücient sampling of the conformational degrees of freedom, which remain trapped in metastable substates. We have recently shown that thermodynamic integration (TI) or free energy perturbation (FEP) can be combined with the driven adiabatic free energy dynamics (dAFED) method, in order to enhance conformational sampling along a set of chosen collective variables. The resulting TI-dAFED or FEP-dAFED methods have been validated on a two-dimensional analytical problem as well as by calculating the enantiomerization free energy of the alanine dipeptide in explicit solvent.

Force field integration

swissparam_logo In 2010, I teamed up with the Gromacs developers to integrate Charmm27, one of the most popular force fields, to the Gromacs molecular dynamics package. The new implementation was rigorously tested on protein and nucleic acid systems. 

In parallel, together with Vincent Zoete at the Swiss Institute of Bioinformatics, we developed the SwissParam web server. For any small molecule, this service provides quick generation of topology and force field files that can be used directly within the Charmm and Gromacs softwares.

Development of peptide inhibitors for MAP kinases

In a collaboration between the Molecular Modeling Group at the Swiss Institute of Bioinformatics and the (now defunct) pharmaceutical company Xigen, we developed peptide inhibitors for several MAP kinases. Using binding free energy decomposition methods (and chemical intuition), we proposed peptides including peptidase-resistant D-amino acids. These peptides were then synthesized and tested in vitro by Xigen, and further optimized through several rounds of modelization and measurements. Note that these results were never published due to intellectual property issues.  mapk inhibiitor

T cell receptor / peptide-MHC interactions

The group of Olivier Michielin has an ongoing interest in understanding the mechanisms underlying T cell activation through T cell receptor (TCR) binding to specific peptide-MHC proteins on the surface of antigen-presenting cells. As part of this effort, we conducted an extensive steered molecular dynamics study of three related TCR-pMHC complexes.

In a first part of this study we developed the individual steering scheme in which proteins are pulled apart while their overall structure is preserved. We then tried to apply the Jarzynski identity to calculate absolute binding free energies for these TCR-pMHC complexes, based on a large number of slow nonequilibrium unbinding trajectories. The results illustrated the now well-recognized convergence difficulties of the Jarzynski identity for processes with large activation free energies.

In the second part of this study, we took advantage extremely large steered molecular dynamcics data sets to calculate average values of several observables as a function of the TCR-pMHC distance. These observables include energetic components, number of H-bonds or hydrophobic contacts and the localization of trapped water molecules.

Nonequilibrium statistical mechanics

jarzynski identity My Ph.D thesis at ETH Zurich focused on two complementary aspects of molecular dynamics: thermostating and nonequilibrium simulation. In particular, the Jarzynski identity states that the equilibrium free energy of a process can be reconstructed by averaging the external work performed in many nonequilibrium realizations of the process. In such nonequilibrium simulations, the excess heat is extracted from the system by the thermostat used to generate the desired thermodynamical ensemble. The central theoretical results was a proof of the Jarzynski identity based on the specific equations of motion used in thermostated molecular dynamics, without any further assumptions.

Here you can download my PhD thesis.