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$Id: biomedical.m4 228 2010-05-30 19:50:28Z akohlmey $ $Id: icms.m4 199 2010-02-20 01:34:18Z akohlmey $
Research on anesthetics at the ICMS focuses on the mechanisms by
which volatile and intravenous general anesthetics modulate ion
channels.
nAChR: We have proposed that cholesterol (which is required for nicotinic acetylcholine receptor function) is deeply embedded in the transmembrane portion of the structure, and developed a model of a cholesterol-nAChR complex suitable for computational use. This model has been evaluated in simulations ranging up to 500 ns in length, and shown to significantly stabilize the receptor with respect to the control system.
K2P: We have built a model for the anesthetic-sensitive tandem pore domain potassium channel TREK-1, including the cytoplasmic domain. Although the cytoplasmic domain is initially constructed as a dimer extending into the cytoplasmic region, multiple simulations demonstrate that it docks as two monomers to the intracellular leaflet of charged lipid bilayers.
Recently, CHARMM-compatible models for isoflurane and propofol have
been developed within our group. Isoflurane parameters are available
here,
while propofol parameters are available upon request. Both models
reproduce correct solvation free energies in TIP3P solvent.
In this method, a high concentration of the anesthetic is placed in the aqueous phase of the simulation and allowed to partition into membrane and protein binding sites until a clinical concentration in water is reached. We have very recently provided detailed visual images of binding sites for isoflurane on nAChR and the homologous prokaryotic channel GLIC, demonstrating that the primary method of inhibition by isoflurane in these two channels is likely via pore-block. We are presently investigating the effect of isoflurane bound to potentially allosteric sites on nAChR dynamics.
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The M2 protein from influenza virus A is a proton channel, responsible for the acidification of the interior of the virion. This process is required for the release of the genetic material into the host cell. Its inhibition constitutes one of the major strategies for treating influenza, and as such it is the target of two of the four available flu drugs. Unfortunately the recent emergence of drug-resistant strains has neutralized these two drugs. Despite the fact that the recent determination of the channel structure has greatly increased our understanding of the function of M2, much of molecular mechanism of proton transport and of drug-resistance remains to be elucidated.
A full treatment of the dynamics of M2 is intrinsically challenging, however, because important events in the transport cycle occur on very different timescales and require different levels of description to model them accurately. Fast proton transfer processes are intrinsically coupled to much slower motions which are responsible for conformational changes in the protein. We adopt a combined approach involving experimental biophysics and theoretical investigations based on classical and hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations. Our work elucidates the mechanism for proton transport in M2, where the protonation of specific pore-lining residues results in structural changes in the protein and pore waters.
The design of effective anti-flu drugs requires a thorough understanding of the molecular mechanisms governing protein-drug binding and, more importantly, drug-resistance. The lack of structural information on the protein-drug complex, in particular for the S31N drug-resistant mutant, makes MD simulations a suitable approach to study the equilibrium configuration of channel-binding compounds. In order to capture the physico-chemical features impacting on the binding capabilities of a drug molecule, we use classical molecular dynamics simulations, complemented with approaches able to increase the sampling of rare events such as ABF and metadynamics, to screen libraries of compounds of known affinity.
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Misdirected protein phosphorylation is frequently associated with human diseases, particularly cancer, neurological disorders, HIV, and diabetes. Over the last decade, there has been a growing interest in applying protein kinase inhibitors in cancer therapy. The first generation of protein kinase inhibitors use a traditional approach with a small drug molecule blocking the active site and is primarily targeting the cyclin dependend kinase 9 (CDK-9) activity. CDKs and their cyclin partners form a heterodimer, in which the CDK contains the enzymatic domain and the cyclin is the regulatory domain.
The goal of the project is to find more selective and specific ways to control CDK activity by regulating protein-protein binding instead. To that effect, novel drugs have to be designed on the basis of binding maps computed from all-atom and coarse grain molecular dynamics simulations.
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Pathogenic bacteria contain two-component systems (TCS) that sense the environment within a host and activate mechanisms related to antimicrobial resistance. Unraveling how binding of their ligands on the outside of the cell transmits a signal to the inside would help to understand the mechanisms of signal transduction.
This work is done in collaboration with Prof. William F. DeGrado (University of Pennsylvania)
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