Get3, a homodimer at the center of the guided entry of tail-anchored (TA) proteins pathway, leverages energy gained through ATP binding and hydrolysis to undergo large conformational changes from �open� to �closed� states that are necessary for the transport of TA proteins.   To address the thermodynamics of this opening/closing pathway, we have performed a series of conventional and accelerated molecular dynamics simulations of Get3 in multiple nucleotide states, complemented by rigorous free energy calculations.  Results agree well with experiments on the stability of open and closed conformations in the experimentally observed nucleotide states, reveal their populations in the single nucleotides cases, and show good agreement to the recently observed 'semi-open'' state.  In addition, we observe evidence for a new, 'wide-open'' conformation.  These calculations describe the mechanism by which nucleotide binding influences the thermodynamics of Get3 and expands our understanding of the role conformational transitions play in its cellular functions.

Free energy calculations reveal the influence of nucleotide binding on the mechanism of Get3

243rd National Meeting (2012)

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