Klauda Earns NSF CAREER Award

illustration of structural changes in cell membrane proteins

Shown in this figure is the result of the Klauda Group's new enhanced simulation technique to probe structural changes in the lactose transporter of E. coli from its known structure (inward-facing) to a previously unknown structure (outward-facing). Protonation of residue Glu269 was found to be important in transitioning from the inward- to outward-facing state.

A proposal to use the first all-atom technique to predict, in an unbiased manner, the structural transitions that occur in proteins that transport molecules though cell membranes has earned Department of Chemical and Biomolecular Engineering assistant professor Jeffery Klauda a 5 year, $688, 313 National Science Foundation (NSF) Faculty Early Career Development (CAREER) Award. The NSF CAREER program supports the career development of outstanding junior faculty who most effectively integrate research and education within the goals and missions of their programs, departments, and schools.

Klauda studies the ways in which cell membrane transport proteins act as gatekeepers, allowing helpful molecules in, and expelling or denying entry to harmful ones. They accomplish this by reconfiguring their conformations, or structures: they are either open to the outside or to the inside of the cell. After collecting a molecule, they "swing shut" on that end, "swing open" on the other, and expel it on the opposite side, like a revolving door designed for a single person. Klauda's research group has been developing a novel computer simulation technique that visualizes, explains and predicts the proteins' behaviors.

Klauda's award-winning proposal, "Secondary Active Membrane Transporters: Determining Protein Structure and Transport Mechanism with a New Hybrid Simulation," outlines his plan to investigate how a class of proteins called secondary active transporters (SATs) interact with cell membranes. In most cases, only one conformational state is known for each SAT, but their transport cycles require several conformations in order to move their molecular cargo. The objective of the research is to investigate the transport mechanisms and multiple conformational changes of several SATs though the use of a new simulation method called "implicit-explicit membrane simulation."

"We've extended an existing technique developed at the National Institutes of Health called self-guided Langevin dynamics, or SGLD, that enhances motions based on a random guiding force," explains Klauda. "Although this has been used in peptide [short amino acid sequences] folding studies, we were the first to successfully extend it to significant changes in a large transmembrane protein. The novelty of our approach is that SGLD is only used to obtain conformations that are placed in an all-atom explicit membrane model of E. coli. These are then simulated with molecular dynamics to obtain equilibrated structures that closely match the environment in the cell."

"The exciting part of research," he adds, "is that we will be able to provide a clearer picture of membrane protein transport cycles that have eluded scientists for nearly all SAT proteins. Obtaining high-resolution crystal structures of SAT proteins is extremely tricky. Our new discoveries will certainly complement those in traditional protein structural determination."

In addition to contributing to our fundamental understanding of protein transport in the cell membranes of mammals, plants and single-celled organisms, Klauda's work may also shed light on problems such as why and how drug-resistant cells expel antibiotics.

Klauda feels the University of Maryland has been an excellent place to launch his academic career. "The computational support provided by the Office of Information Technology's Deepthought High Performance Computing Cluster has allowed my students to focus on science and provides ample resources for our computationally demanding studies," he says. "UMD's closeness to national labs like the NIH and NIST has enhanced our ability to collaborate with their experimentalists and theoreticians."

For More Information:

Visit Professor Klauda's web site »

See Pendse, P. Y., Brooks, B. R., and Klauda, J. B. (2010). Probing the Periplasmic-Open State of Lactose Permease in Response to Sugar Binding and Proton Translocation. JMB 404, 506:521 »

Published August 27, 2012