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                       BIOINFORMATICS COLLOQUIUM
                    School of Computational Sciences
                        George Mason University
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          Continuum Electrostatics and Membrane Peptides/Proteins
                           Wonpil Im, Ph.D.
                     Scripps Research Institute

                      Thursday, March 18, 2004
                              3:00 pm
                 PW2  Auditorium, Prince William Campus

Exploiting recent developments in generalized Born (GB) electrostatics
theory, we have reformulated the calculation of the self electrostatic
solvation energy to account for the influence of biological membranes.
Consistent with continuum Poisson-Boltzmann (PB) electrostatics, the
membrane is approximated as an solvent-inaccessible infinite planar
low-dielectric slab.  The present membrane GB model closely reproduces
the PB electrostatic solvation energy profile across the membrane.  The
nonpolar contribution to the solvation energy is taken to be
proportional to the solvent-exposed surface area (SA) with a
phenomenological surface tension coefficient.  The proposed membrane
GB/SA model requires minor modifications of the pre-existing GB model
and appears to be quite efficient.  By combining this implicit model for
the solvent/bilayer environment with advanced computational sampling
methods, like replica-exchange molecular dynamics, we are able to fold
and assemble helical membrane peptides.  We examine the reliability of
this model and approach by applications to three membrane peptides:
melittin from bee venom, the transmembrane domain of the M2 protein from
influenza A (M2-TMP), and the transmembrane domain of glycophorin A
(GpA).  In the context of these proteins, we explore the role of
biological membranes (represented as a low-dielectric medium) in
affecting the conformational changes in melittin, the tilt of
transmembrane peptides with respect to the membrane normal (M2-TMP),
helix-helix interactions in membranes (GpA), and the prediction of the
configuration of transmembrane helical bundles (GpA).  The present
method is found to perform well in each of these cases and is
anticipated to be useful in the study of folding and assembly of
membrane proteins as well as in structure refinement and modeling of
membrane proteins where a limited number of experimental observables are
available.

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