Atomistic Mechanism Underlying the Regulation of the GPA1 G Protein Signaling Pathway Mediated by the Gibberellin A1 Phytohormone Binding to the GCR1 Plant G-Protein-Coupled Receptor

Creators: Hernández, Pedro M.¹; Arango, Carlos A.²; Kim, Soo-Kyung³; Jaramillo-Botero, Andrés^{3, 1}; Goddard, William A., III³

1. Pontificia Universidad Javeriana
2. Icesi University
3. California Institute of Technology

Abstract

We propose an atomistic mechanism suggesting that fundamental plant processes, including seed germination, root elongation, and flower and fruit production, may be regulated by phytohormones such as Gibberellin A1 (GA1) binding to the GCR1 plant G-protein-coupled receptor. This parallels the central roles of GPCRs in animals for vision, taste, smell, pain, depression, and nerve signaling, among others. Validating GCR1 as a genuine GPCR in plants, particularly its interaction with GPA1, G-protein, would mark a groundbreaking advancement in understanding plant processes, both biologically and agronomically. However, experimental confirmation of this interaction and evidence supporting the idea that binding of GA1 to GCR1 would regulate GPA1 activation are lacking. Indeed, the design of experiments to explore these hypotheses is impeded by the absence of structural information relating to interactions of GPA1 with the GA1-GCR1 complex. To address this gap, we employ molecular dynamics and metadynamics simulations to demonstrate that binding GPA1 to the GA1-GCR1 complex induces conformational changes that open up the Ras and Helical domains of GPA1 to release GDP for exchange with GTP, thereby enabling signaling. Our results suggest numerous mutations involving GA1 binding at the GCR1 site and the coupling of GCR1 to the GPA1 G-protein that could be used to validate (or not validate) our predicted mechanism. Such validation would serve as a foundation for devising strategies to design novel agonists and inverse agonists to provide precise control of crucial plant processes.

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Acknowledgement

W.A.G., A.J.B., and S.K.K. received support from NIH (R01HL155532). S.K.K. and W.A.G. 23 also received support from NIH (R01HL155532). P.M.H. and C.A.A. were funded partially by the OMICAS alliance/Pontificia Universidad Javeriana Cali and Universidad Icesi, respectively. The OMICAS acronym stands for “In-silico Multiscale Optimization of Sustainable Agricultural Crops”, a member of the Scientific Colombia Ecosystem, sponsored by the World Bank, and the Colombian Ministries of Science, Technology and Innovation (Minciencias), Education, Industry and Tourism, and the ICETEX. Project ID: FP44842-217-2018.

Data Availability

This repository contains all the files required to perform metadynamics calculations and molecular dynamics simulations using the NAMD software. The information collected here is organized to facilitate the reproduction of simulations and the analysis of results related to the GA1-GCR1-GPA1-GDP-Mg²⁺ complex. Included files: Input files for metadynamics calculations: Configurations, and input files needed to run metadynamics simulations. Parameter Files: Include specific parameters for simulations of the complex studied. Structural files (.pdb and.psf): Initial structures of the GA1-GCR1-GPA1-GDP-Mg²⁺ complex, required for setting up the simulations. Metadynamics results: .pdb files corresponding to the configurations with the lowest free energies obtained from the metadynamics calculations. Files for molecular dynamics simulations: Inputs, parameters, and selected structures (pdb and psf), as the lowest-energy configurations from the metadynamics simulations to be used in molecular dynamics simulations. The goal of this repository is to provide a comprehensive and accessible resource for those interested in replicating or building upon this work for future molecular simulation studies. https://github.com/iomicasjaverianacali/Metadynamics.

Supplemental Material

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.jcim.4c01734.

Detailed description of the results of the metadynamics and MD simulations on newly constructed GA1-GCR1-GPA1 complexes, and the thermodynamic analysis of the inactive, partially active, and fully active structures of GPA1 bound to the GA1-GCR1 complex (PDF)

ci4c01734_si_001.pdf (7.44 MB)

Contributions

P.M.H. was responsible for all calculations, the creation of graphs and tables, and the writing of the initial draft. He also participated in editing the manuscript. Additionally, P.M.H. conducted the literature review, data analysis, and coordinated the research activities. W.A.G., A.J.-B., C.A.A., and S.-K.K. contributed to the conceptualization of this paper and served as advisors to P.M.H. They provided critical feedback and helped shape the research, analysis, and manuscript. They also assisted in editing the manuscript.

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