BIOL-TRANSP-COMPUT

Mechanisms of transport across biological membranes

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Proteins are integral to smooth body functioning as they transport important molecules across cell membranes. An EU- project will comprehensively study three proteins to understand their structure and function in health and disease.

Descrizione progetto (Article)

The 'Mechanisms of transport across biological membranes' (BIOL-TRANSP-COMPUT) consortium are investigating the dynamics of membrane protein function. The three proteins selected for this study are SecA motor protein, AHA2 plasma membrane proton pump and the rhodopsin family of proteins. Computer simulations and modelling of these proteins should reveal the role of membrane proteins, lipids, chemo-mechanical coupling and protonation dynamics in mediating transport.

Protonation is the addition of a proton to a substance, thereby making it more acidic. This process of hydrogen bonding is critical in proton transfer systems and protein conformations to enable the transport of molecules across cell membranes. Project scientists successfully published three papers on the role of hydrogen bonding and certain amino acids in membrane protein function as well as proton-coupled dynamics.

SecA uses adenosine triphosphate (ATP)-dependent chemo-mechanical coupling to translocate proteins across membranes in bacteria using the SecYEG protein channel. Bioinformatics and sequence analyses along with SecA dynamics computations provided novel insight in this area. Certain mutations were found to affect interaction within the DEAD region associated with ATP domain. Results are to be disseminated through publication.

The AHA2 plasma membrane proton pump belongs to the P-type ATPases family. They are complex enzymes that act as secondary transport systems by long-distance conformational coupling. Assessing protonation dynamics could potentially reveal the functional role of specific amino acids. Project outcomes have culminated in a Master's thesis on the AHA2 plasma membrane proton pump. Simulations demonstrated that the structure and dynamics of the pump depend heavily on the protonation state of the pump.

Rhodopsins are light-sensitive retinal proteins. Systematic molecular dynamics simulations revealed that rhodopsin mutations can significantly affect water dynamics inside the protein. These results are being written up for publication, whereas the outcomes of studies on retinal torsional barriers have already been published.

Project research has contributed to the training of graduate and undergraduate students, and results have been disseminated via research seminars and publications. Study outcomes could have significant impact on drug design and biomedical research in areas such as optogenetics.