We use computational tools to study biomolecule electrostatics and charge transfer in biological systems. These are our current research topics.

Ion channels

ion channelIon channels are membrane proteins that form pores and control the flow of ions across cell membranes. They are found in virtually all living cells, and have tremendous physiological relevance in regulating ion concentrations inside cells. In the brain and the heart, ion channels are key players in generation of exotic phenomena known as action potentials.

One of the topics we currently study is how ion channels are regulated by pH. The relationship between ion concentrations inside and outside of a cell, pH, and activity of a channel is a complicated one. Our recent paper has shown how modulation of the number of ions bound in the channel pore can affect the number of protons that bind to it. In short, protons can compete with positive ions. In turn, binding of protons can module the conductance of a channel.

Protein electrostatics

Aspartic acidBinding of protons to ionizable amino acids in proteins, such as aspartic and glutamic acid, histidine and lysine affects the charge on that residue and thus determines the protein’s electrostatic properties. Electrostatics affects almost every structural and functional aspect of proteins; including stability, solubility, dynamics, interactions, and catalysis. It is especially important for key processes involving movement of charges, including proton and electron transfer reactions and transport of ions. Thus it is very important to know how many protons are bound to a protein, and to which ionizable residues, i.e., it is important to know what the protonation state of each ionizable residue is.

We are developing new methodologies for better modeling of protonation (i.e., charge) states of ionizable residues in molecular dynamics (MD) simulations. In MD simulations protein dynamics can be simulated as a function of time, however, the protonation states of ionizable residues have to be fixed, and in some cases it is not obvious what they should be.  In MD simulations at constant pH, the protonation state can change during dynamics. To perform such simulations in explicit water is a real challenge, and we have developed a method for that. We are also tackling challenges in sampling of conformations in constant pH simulations, through pH replica exchange simulations, and pH replica exchange with reservoirs of conformations.