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Biomolecular Simulations Group

Membrane transport

Membrane transporters rely on large-scale conformational changes for their function (see the schematic figure on the right for a simplified transport process and the diverse conformational states involved in it). Despite considerable effort, however, details of such structural transitions are largely unknown due to their complex nature, slow dynamics, and both experimental and computational limitations. I have recently developed a novel approach to characterize the conformational transitions of membrane transporters at an atomic level. The methodology which is based on a combination of several nonequilibrium molecular dynamics techniques has been employed to study several proteins from primary and secondary transporter families such as ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporters, respectively. The novel sampling strategy developed for these projects relies on (i) our knowledge of the transition, e.g., from low-resolution experimental data, (ii) nonequilibrium statistical mechanics, and (iii) large-scale multiple-copy algorithms well-suited for petascale supercomputing resources.

ABC transporter MsbA

MsbA is a bacterial homolog of human multidrug resistance P-glycoprotein whose overexpression is one of the most common causes of resistance to the drugs used in the chemotherapy for cancer patients. We studied MsbA transporter using novel system-specific reaction coordinates and simulation protocols which resulted in an unprecedented level of detail on the nature of conformational coupling and the mechanism of transport. The results indicate that the opening of the cytoplasmic gate during the outward- to inward-facing transition of apo MsbA is disfavored when the periplasmic gate is open and facilitated when the nucleotide-binding domains undergo a twisting motion that involves a dramatic change in their relative orientation. These results appeared in Proc. Natl. Aca. Sci. which was recommended by Faculty of 1000 and highlighted by several news websites and blogs. The novel methodology used in this work was also described in more detail in another publication which appeared in J. Chem. Theory Comput.

MFS transporter GlpT

Employing a novel combination of free energy calculation methods and path-finding algorithms in an iterative approach, we have been able to characterize the entire transport cycle of glycerol-3-phosphate transporter (GlpT). Besides the state associated with the (only) crystal structure of GlpT, we identified several other significant basins in the free energy landscape of GlpT-phosphate complex. Our results indicate that the binding of the substrate lowers the conformational free energy barrier between inward- and outward-facing states. More importantly, the extensive sampling allowed us to identify important residues involved in substrate binding and conformational changes. This work appeared recently in Nature Communications.
Conformational Landscape
Conformational Landscape
Conformational Landscape

Copyright © 2015, Biomolecular Simulations Group, Department of Chemistry and Biochemistry, University of Arkansas.
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