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Our primary research interest is understanding the function of ion channels - membrane proteins that are responsible for electrical signaling in nerves and muscles. We are also interested in exporting the hierarchical approach developed for description of ion channels to other biomolecular processes such as protein-protein interactions and protein aggregation.


	A picture of the simplest ion channel known - antibacterial gramicidin A. It conducts monovalent cations at near diffusion rates, causing collapse of the membrane potential and killing hapless bacteria. Here Gramicidin A (helical dimer in red) is embedded in lipid bilayer (only the phosphate head groups in green are shown) and solvated with a KCl solution (K blue, Cl red and water is in the background). Because of its simplicity, gramicidin offers an ideal channel structure for testing new methods and ideas.

The only method that is fast enough to allow computation of conductance of an ion channel is Brownian dynamics (BD). We use molecular dynamics (MD) and ab initio methods to justify the BD method and derive the model parameters. Some specific projects on ion channels within this general framework are:

Test of molecular dynamics force fields: The traditional force fields ignore polarization interaction, which should play an important role in ion permeation where ions move from bulk water (high dielectric) to protein-lipid interior (low dielectric). Comparison of free energy profiles of ions obtained from MD simulations with and without polarization interaction will provide a test of this conjecture.

Test of continuum electrostatics in channels: Channels are quite narrow (a few A in radius), so it is not clear from the outset that the Poisson equation can be used to determine the forces acting on ions. Comparison of the potential energy of ions from continuum electrostatics with that obtained from MD simulations will reveal at what radius it breaks down.

The role of protein flexibility in ion permeation: Proteins are not rigid structures but whether their fluctuations are coupled to ion permeatin is not well established. Comparison of potential energy calculations with fixed and flexible channel structures will shed light into this question.

Exploiting temperature dependence in biomolecular processes: Temperature has a profound effect on many biological processes but due to lack of a proper theoretical framework to analyse and interpret results, it is rarely used in experimental studies. The project will attempt to develop the necessary formalism to understand the origin of the extraordinary temperature dependence of conductance in ion channels.

Modeling of HERG potassium channels: HERG channels play a significant role in normal heart function, therefore understanding their operation is important for finding cures for heart diseases. The novel aspect of this project is that a flexible amino acid chain is implicated in its inactivation, and hence a new BD formalism need to be developed to describe its dynamics.

Modeling of ClC chloride channels: ClC channels have the unique property that Cl ions themselves are the gating agents. Description of this property requires incorporation of a flexible side chain in the BD simulations as a Brownian rotor, which has not been done so far.

Binding and block of channels by molecules (toxins, drugs, etc): This project is a prelude to a general study of protein-protein interactions. The well-defined binding sites in channels greatly simplifies the docking problem, allowing development of the hierarchical BD/MD approach in a simple setting. Potential applications of such a method in pharmacology are numerous.

Protein aggregation in bulk and membranes: Aggregation of proteins is responsible for many neurological diseases (e.g. Alzheimer). Because it involves large space-time dimensions, a hierarchical approach is the only way to attack this problem.