Globally worsening drought conditions pose an increased threat to agriculture productivity and food security. In plants, hormone abscisic acid (ABA) signaling pathway regulates water stress resistance and is a key target for agrochemical control of drought resistance. Recent structural and biochemical studies shed light on ABA signaling network, however provide limited information about the dynamics of ABA binding to receptor and conformational change of receptor protein. The origins of varying ABA and ABA analogues binding affinities to different class of receptors have been elusive. Here, we utilize extensive molecular dynamics (MD) simulations (500-600 µs aggregate) and Markov state models (MSMs) to uncover the binding pathways of ABA and its analogues, pyrabactin and quinabactin, to different class of receptors in <i>Arabidopsis thaliana</i> and the structure transitions of receptors that occur in response to binding of the ligands. We also report the binding free energy landscapes along these binding pathways, allowing for a thorough investigation of the binding thermodynamics and kinetics of ABA and its analogues. Our results suggest that ABA binding is necessary but not sufficient condition for receptor activation. The major free energy barrier to ABA binding appears to reflect the substantial dewetting of both ABA and the receptor taken place as ABA binds to the receptor. Finally, we explain the inhibition of ABA signaling due to posttranslationally modified receptors by tyrosine nitration. Our results suggest that the newly formed hydrogen-bonding interactions with the nitrated tyrosine inside the binding pocket block ABA binding pathways. Our work demonstrates the power of long timescale MD simulations and MSM framework in elucidating the detailed mechanism of the activation of plant drought resistance signaling and the molecular origins of ligand selectivity. Our findings will facilitate informed genetic manipulation of ABA receptors and improved design of new ABA mimicking agonists.

Complex dynamics of hormone perception and receptor activation in plant drought resistance signaling

256th National Meeting (2018)

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