Living cells depend on the correct functioning of proteins that transport cargo across the membranes. We will use computer simulations to understand the mechanisms employed by three proteins that mediate transport across biological membranes. Each of these three proteins is important for physiology and disease.
A large part of the research planned aims at understanding the SecA motor protein. SecA is an essential component of the Sec translocation system in bacteria, where it couples the hydrolysis of adenosine triphosphate (ATP) with remarkable protein conformational changes to transport newly synthesized proteins across the plasma membrane. Key open questions concern the mechanism of the chemical-mechanical coupling employed by SecA, and how SecA works together with the SecYEG protein channel to translocate proteins. We will address these questions by performing molecular dynamics computations at the classical and combined quantum mechanical/molecular mechanical levels, and bioinformatics analyses.
The plasma membrane proton pump is a member of the P-type ATPases family, complex enzymes essential for maintaining the plasma membrane potential and for secondary transport systems in eukaryotes. We will assess the dynamics of the AHA2 plasma membrane proton pump in a hydrated lipid membrane, the mechanism of long-distance conformational coupling, and the functional role of specific amino acids.
Channelrhodopsin-2 is a light-gated cation channel that can be expressed in mammalian neurons and used as a powerful tool to probe neuronal circuits. Comparison of the sequences of channelrhodopsin-2 and other microbial-type rhodopsins raises intriguing questions about the functional roles of specific amino acids. To contribute to the general understanding of the principles that govern the design of membrane transporters, we will combine homology modeling of channelrhodopsin-2 with molecular dynamics of channelrhodopsin-2, bacteriorhodopsin, and sensory rhodopsin.
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