The atomistic Mechanism Underlying Regulation of the GPA1 G Protein Signaling Pathway Mediated by Abscisic Acid (ABA) Phytohormone Binding to the GCR1 Plant G Protein Coupled Receptor

We propose an atomistic mechanism by which key
plant processes, including seed dormancy, root elongation, secondary
root proliferation, and flower and fruit produc-tion, are regulated. This
regulation occurs through binding of the phytohormone abscisic acid
(ABA) to the plant G protein-coupled receptor (GPCR) GCR1. This
mirrors the central role of GPCRs in animal systems, where they
mediate vision, taste, olfaction, pain perception, and neurotransmission.
Establishing GCR1 as a bona fide GPCR in plants would
represent a transformative advance in plant biology and agriculture. In
particular, GCR1 would be shown to transduce ABA signals through
interaction with the Gα subunit (GPA1). However, direct
experimental evidence for this interaction and conformation that
ABA binding to GCR1 modulates GPA1 inactivation, remains elusive.
A major obstacle in testing these hypotheses is the lack of structural data on GPA1 interactions within the ABA-GCR1 complex. To
address this gap, we employ molecular dynamics (MD) and metadynamics simulations based on the AMBER and CHARM31 force
fields to characterize atomistically the ABA-GCR1-GPA1 ternary complex. Our MD simulations reveal an allosteric mechanism
whereby GCR1-ABA binding induces a rigid-body closure of the GPA1 Ras and α−helical domains, creating a steric blockade that
traps GDP in the nucleotide-binding pocket. This con-formation prevents GTP exchange and maintains GPA1 in an inactive state,
effectively terminating the signaling cascade. Free energy landscape analysis further demonstrates that this closed state represents a
deep energy minimum, suggesting biological relevance as a regulatory mechanism. We propose specific mutations in the ABAbinding
site of GCR1 and at the GCR1-GPA1 interface that could experimentally validate (or refute) our proposed mechanism.
Confirmation of this model would pave the way for designing novel agonists and inverse agonists to precisely manipulate critical
plant processes.