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Development of free energy simulation approaches

O. Michielin


Free energy calculations using statistical mechanics of nonequilibrium systems

M. Cuendet and O. Michielin  

Binding free energy calculation for the TCR-pMHC complex using the Jarzynski identity.

During his Ph.D, Michel Cuendet studied two complementary aspects of molecular dynamics: thermostating and nonequilibrium simulation. Molecular dynamics provided a new field of application for the statistical mechanics of nonequilibrium systems. The most famous example is Jarzynski's identity, which 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. The excess heat created by the dissipative part of the work needs to be extracted from the system by a thermostat, which preserves the right thermodynamical ensemble. On the theoretical level, Michel looked at the accurate way do estimate the temperature within a discrete (leap-frog) time evolution algorithm. He provided a new proof of the Jarzynski identity for the specific equations of motion used in thermostated molecular dynamics. The main application was to assess the performance of the Jarzynski method to determine the unbinding free energy profile of a big protein-protein complex. The system of choice was the TCR-pMHC complex (see picture). Michel's interests include nonequilibirum statistical mechanics, free energy methods in general, as well as docking algorithms.


M. A. Cuendet, O. Michielin, "Application of the Jarzynski identity to protein-protein dissociation in molecular dynamics: The TCR-pMHC complex", in preparation
M. A. Cuendet, W. F. van Gunsteren, "On the calculation of velocity-dependent properties in molecular dynamics simulations using the leap-frog integration algorithm", submitted to J. Chem. Phys. (2006)
M. A. Cuendet, "The Jarzynski identity derived from general Hamiltonian or non-Hamiltonian dynamics reproducing NVT or NPT ensembles", J. Chem. Phys. 125 : 144109 (2006)
M. A. Cuendet, "Statistical mechanical derivation of the Jarzynski identity for non-Hamiltonian thermostated dynamics", Phys. Rev. Lett. 96(1) : 120602 (2006)
A. Labbi, M. Cuendet, "Predictive Data Mining for Project Portfolio Risk Management" in "Handbook of Integrated Risk Management for E-Business : Measuring, Modelling, and Managing Risk", J. Ross Publishing (2005), p. 151 (ISBN 193215907X)
M. Cuendet, A. Labbi, "Consistent AdaBoost for boosting stumps", Proceedings of the International Conference on Machine Learning and Applications - ICMLA 2002, Las Vegas, Nevada, USA. CSREA Press (2002) p. 117
M. Cuendet, A. Labbi, "Some theoretical and practical perspectives on boosting weak predictors", IBM Research technical paper RZ3402 (2002)
A.Labbi, M. Cuendet, "Boosted decision trees for project risk assessment and pricing", IBM Research technical paper RZ340 (2002)


Approaches to describe ligand-protein interactions and protein enzymatic activity

S. Bernèche and O. Michielin  

My work at SIB aims at calculating/predicting ligand-protein affinities from ab initio principles. It involves calculating absolute free energy of binding using different simulation approaches based on explicit molecular dynamics (free energy decomposition through perturbation simulations, potential of mean force describing the ligand-protein association, ...). These methods are notably applied to the study of inhibitors of the Indoleamine Dioxygenase, a new cancer immunossuppression target.


G. Lamoureux, M. L. Klein and S. Bernèche. A stable water chain in the hydrophobic pore of the AmtB ammonium transporter, Biophys. J. (Submitted)
S. Bernèche and B. Roux. A gate in the selectivity filter of potassium channels. Structure 13, 591-600 (2005).
L. Zheng, D. Kostrewa, S. Bernèche, F. K. Winkler and X.-D. Li. The mechanism for ammonia transport based on the crystal structure of AmtB of E.Coli. Proc. Natl. Acad. Sci. 101(49), 17090-17095 (2004)
S. Y. Noskov, S. Bernèche and B.Roux. Control of ion selectivity in potassium channels by electrostatic and dynamic properties of coordinating ligands. Nature 431, 830-834 (2004)
S. Bernèche and B. Roux. A microscopic view of ion conduction through the K+ channel. Proc. Natl. Acad. Sci. 100(15), 8644-8648 (2003)
S. Bernèche and B. Roux. Energetics of ion conduction through the K+ channel. Nature 414, 73-77 (2001). News &Views: C. Miller. See potassium run. Nature 414, 23-24 (2001)

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