Sun, June 19, 2011
Dr. Magnus Andersson obtained his Ph.D. in 2009 from Chalmers University of Technology in Sweden where he developed a time-resolved X-ray methodology for visualizing membrane protein dynamics in solution. As a natural consequence of his strong interest in structural biology and protein dynamics, he has now entered the field of molecular dynamics (MD) simulation. In order to unveil the complex structural-functional relationships of biological macromolecules, a combined experimental-theoretical approach offers a remarkable advantage. He is currently working as an ICAM Postdoctoral Fellow at the University of California-Irvine with Dr. Stephen H. White as Primary Mentor and Dr. H. Ronald Kaback, UCLA, as Secondary Mentor.
Andersson is investigating the mechanisms of membrane proteins. Membrane proteins are the proteins located in the membrane of cells and organelles. These proteins carry out many important processes, such as transport of different ions and solutes over the membrane. They also provide ways for the cell to communicate with its surroundings. Furthermore, membrane proteins represent 60 percent of all drug targets, which makes the need for understanding their function even more important.
To unravel the exact mechanisms by which these proteins function, Andersson seeks a detailed understanding of how they arrange themselves in the membrane environment. It is possible, although extremely challenging, to determine the structure of a membrane protein by shining X-rays through a crystal containing the protein of interest. This methodology is called X-ray crystallography and has provided invaluable structural knowledge of many membrane proteins (272 structures to date). However, as Andersson points out, “it is important to remember that proteins do not act as merely static entities. Rather, they rearrange structurally so as to optimize their specific function.” By using MD simulations, Andersson can calculate the structural dynamics of a protein according to the laws of physics. Recent advancements in both hardware and software development allow scientists to perform these calculations on a nanosecond to millisecond timescale. This makes MD simulations an extremely powerful tool in the membrane protein field since this is the timescale on which most of these proteins operate.
Lactose permease (LacY) is a membrane protein that couples the transport of sugar and protons over the cell membrane and is, according to Andersson, “a perfect model system for studying the structural dynamics of a membrane protein.” The 3D arrangement of this membrane protein is known, and a wealth of biochemical analyses exists. However, the exact mechanism by which LacY transports sugar and protons is not yet known.
As an ICAM Postdoctoral Fellow, Andersson is performing a set of MD simulations to identify the basic principles that govern the catalytic cycle of LacY. Investigating such a complex system by means of MD simulations calls for certain simplifications. For example, by contrasting two systems that differ in some feature, Andersson can learn what role that particular feature plays. This could be a difference in the kinds of lipids surrounding the protein, a mutation in the protein, or, as in Andersson’s study, different protonation states of amino acids.
Mutational studies have identified a set of amino acids in LacY that are absolutely crucial for transporting protons; this guided Andersson in the selection of amino acids to study. Though removing a proton from one of these residues might not sound like a big enough interaction to elicit anything else than a local structural rearrangement around that particular amino acid, Andersson has found that such an interaction has a profound effect on the structural arrangements of amino acids throughout the entire protein. His simulations reveal that removing a single proton can turn a structurally stable state of LacY into a highly flexible state where even large-scale structural changes are observed. This is typical behavior of a transport protein since it needs to change its structure quite significantly in order to transport substrates from one side of the membrane to the other. So, by using MD simulations, Andersson learns clues as to which are the basic principles underlying the catalytic process of a membrane protein.
Stephen H. White, Andersson’s primary mentor, remarks that Andersson “is an exceptionally promising and talented young scientist. I am delighted that he has agreed to come to my laboratory for postdoctoral research.”
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