Membrane proteins encompass a large and important class of proteins. A molecular understanding of their structure, dynamics, and function is fundamental in biological sciences. Experimental studies of proteins in membrane environments remain very challenging, and computer simulations can provide insight about atomic-level dynamics and functional mechanisms of membrane proteins. We have developed the heterogeneous dielectric generalized Born (HDGB) methodology [J. Chem. Phys. 122, 124706 (2005)], the extension of the GBMV model that can permit the simulation of the transmembrane protein in the implicit membrane environment. We are applying our method to study functions of various types of integral membrane based on their dynamics.

The ABC transporters couple ATP hydrolysis to the transportation of broad range of substrates across cell membranes and has a clinical importance in multidrug resistance of bacteria. The Escherichia coli BtuCD integral membrane protein is an example of an ABC (ATP-binding cassette) transporter importing vitamin B12. Our HDGB implicit membrane simulations are well-suited for simulating a large transmembrane protein such as BtuCD because of the significant reduction in computational cost and complexity inherent in heterogeneous membrane environment. Our research focuses on the transport mechanism of vitamin B12 that may provide the prototypical model in this family of ABC transporters. The movie (7.5 MB mpg movie) shows the 3 ns of the HDGB simulation of BtuCD. The implicit membrane model of a fully hydrated DPPC membrane environment are used in the simulation, and the interface between blue and gray regions indicates the ester group position of lipids.

Cell membranes are impermeable to many compounds that are essential to life including ions. One of key components of maintaining the homeostatic balance is a ion channel that transports ions across membrane barrier. We are developing the methodology in the framework of HDGB model to simulate this class of membrane proteins. Challenges in simulating ion channels involves the treatment of the pore region in membrane proteins. The hybrid simulations of implicit and explicit solvent model are used to tackle this problem by treating the channel regions with explicit water molecules. Gramicidin A ion channel is used as the benchmark for our development because it is one of the best characterized ion channels experimentally and theoretically. The method will be applied to study the other channels such as KcsA, OmpF. The movie (6.5 MB mpg movie) shows the ion permeation through the gramicidin A channel using the HDGB simulation. DMPC membrane environments are modeled implicitly, and the line indicates the top of a hydrocarbon core region. The interface between blue and gray regions indicates the ester group region of lipids.

Understanding of adsorption, distribution, metabolism, and/or excretion (ADME) properties of small molecules are important in drug discovery. The HDGB model is well calibrated for solvation free energetics of small molecules in and out of membrane and has a potential for studying the ADME properties of small drug candidates. The figure shows the solvation free energy profile across membrane of 3-methylindole (tryptophan amino acid analogue). Aromatic residues (Trp, Tyr, and Phe) are known to be located predominantly in the membrane interface regions of membrane proteins. Our HDGB model predicted the location of solvation free energy (&Delta Gslv) minimum of Trp analogue at 16 Å which is just above the ester group region of lipids.