Jasmonates are critical plant hormones, mediating stress response in plants and regulating plant growth and development. The jasmonate receptor is a multi-component complex, composed of Arabidopsis SKP-LIKE PROTEIN1 (ASK1), CORONATINE INSENSITIVE 1 (COI1), inositol phosphate (InsP), and jasmonate ZIM-domain protein (JAZ). COI1 acts as multi-component signaling hub that binds with each component. InsP is suggested to play important roles in the hormone perception. How InsP binds with COI1 and the structural changes in COI1 upon binding with InsP, JA-Ile, and JAZ are not well understood. In this study, we integrated multiple computational methods, such as molecular docking, molecular dynamics simulations, residue interaction network analysis and binding free energy calculation, to explore the effect of InsP on the dynamic behavior of COI1 and the recognition mechanism of each component of the jasmonate receptor complex. We found that upon binding with InsP, JA-Ile, and JAZ1, the structure of COI1 becomes more compact. The binding of InsP with COI1 stabilizes the conformation of COI1 and promotes the binding between JA-Ile or JAZ1 and COI1. Analysis of the network parameters led to the identification of some hub nodes in this network, including Met88, His118, Arg120, Arg121, Arg346, Tyr382, Arg409, Trp467, and Lys492. The structural and dynamic details will be helpful for understanding the recognition mechanism of each component and the discovery and design of novel jasmonate signaling pathway modulators.

Farnesoid X receptor α (FXRα) is a bile acid-activated transcription factor, which plays important roles in the regulation of multiple metabolic processes. Development of FXR antagonist has revealed great potential for the treatment of metabolic disorders. The compound N-Benzyl-N-(3-(tertbutyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino). Benzamide (NDB) was recently determined as a selective antagonist of FXRα, while the detailed interaction mechanism is not well understood. In this study, the combined computational methods including molecular dynamics simulations, binding free energy calculation, and principal component analysis were utilized to investigate the effect of NDB on the dynamics behaviors and dimerization of FXRα The binding free energy calculation indicated that the protein dimerization increases NDB affinity and the binding of NDB also stabilizes the interaction between two subunits of FXRα. Further decomposition of the overall binding free energies into individual residues identifies several residues significant for NDB binding, including Leu291, Met294, Ala295, His298, Met332, Ser336, Ala452, and Leu455. It also suggests that the interactions of L289(A)–W458(B), W458(A)–L289(B), R459(A)–N461(B), and N461(A)–R459(B) are important for the dimer stabilization. This study provides a molecular basis for the understanding of binding mechanism between antagonist NDB and FXRα and valuable information for the novel FXR modulators design for the treatment of metabolic syndrome.

Actin is a highly conserved protein. It plays important roles in cellular function and exists either in the monomeric (G-actin) or polymeric form (F-actin). Members of the actin-depolymerizing factor (ADF)/cofilin protein family bind to both G-actin and F-actin and play vital roles in actin dynamics by manipulating the rates of filament polymerization and depolymerization. It has been reported that the S6D and R98A/K100A mutants of actin-depolymerizing factor 1 (ADF1) in Arabidopsis thaliana decreased the binding affinity of ADF for the actin monomer. To investigate the binding mechanism and dynamic behavior of the ADF1–actin complex, we constructed a homology model of the AtADF1–actin complex based on the crystal structure of AtADF1 and the twinfilin C-terminal ADF-H domain in a complex with a mouse actin monomer. The model was then refined for subsequent molecular dynamics simulations. Increased binding energy of the mutated system was observed using the Molecular Mechanics Generalized Born Surface Area and Poisson–Boltzmann Surface Area (MM-GB/PBSA) methods. To determine the residues that make decisive contributions to the ADF1 actin-binding affinity, per-residue decomposition and computational alanine scanning analyses were performed, which provided more detailed information on the binding mechanism. Root-mean-square fluctuation and principal component analyses confirmed that the S6D and R98A/K100A mutants induced an increased conformational flexibility. The comprehensive molecular insight gained from this study is of great importance for understanding the binding mechanism of ADF1 and G-actin.