(231g) Computational Modeling and Simulation Studies of Ligand Binding Problems

The study of protein-ligand and clay-ligand interactions is a key subject in understanding protein function in biological systems, designing therapeutics, and discovering adsorbent materials for environmental remediation. Computational modeling and molecular dynamics simulations can be coupled with experimental studies to provide an atomistic understanding of such interactions and fill crucial “gaps” by obtaining information that is not accessible from experiments and predicting novel functions.In this talk, we will provide an overview of our computational studies on three example cases of (i) compound-protein, (ii) peptide-protein, and (iii) ligand-clay interactions.

(i) We developed an in-house protocol that can be used to obtain a refined docked model structure of a compound-protein interaction. The protocol consists of the combination of a nearly exhaustive, highly accurate docking procedure and MD simulations and physics-based free energy calculations.We will demonstrate the protocol’s application to examine chemotaxis induced by ligand binding [1], interactions of the aryl hydrocarbon receptor with structurally diverse ligands[2-4], complement C3 ligand inhibitors for autoimmune disorders [5], and demonstrate its performance in comparison to experimental studies.

(ii) We used constrained replica exchange MD simulations in tandem with experiments to study the binding of peptide GAIPIG to amyloid-β[6]. We will provide computationalinsights on the study of interactions formed by the peptide with amyloids and demonstrate how analogous investigations can be used to discover novel peptide inhibitors.

(iii) We used a combination of computational modeling and simulations in tandem with experiments to study the binding of toxic compounds to clays to provide atomistic insights on how clays can be used as adsorbents of toxic compounds. We will provide an overview of our simulations and results and demonstrate how our studies can be used to screen toxic compounds that can be captured by clays.

[1] Orr AA, Jayaraman A, Tamamis P. Molecular Modeling of Chemoreceptor:Ligand Interactions. Methods Mol Biol. 2018;1729:353-372.

[2] Cheng Y, Jin UH, Davidson LA, Chapkin RS, Jayaraman A, Tamamis P, Orr A, Allred C, Denison MS, Soshilov A, Weaver E, Safe S. Editor's Highlight: Microbial-Derived 1,4-Dihydroxy-2-naphthoic Acid and Related Compounds as Aryl Hydrocarbon Receptor Agonists/Antagonists: Structure-Activity Relationships and Receptor Modeling. Toxicol Sci. 2017;155(2):458-473.

[3] Jin UH, Park H, Li X, Davidson LA, Allred C, Patil B, Jayaprakasha G, Orr AA, Mao L, Chapkin RS, Jayaraman A, Tamamis P, Safe S. Structure-Dependent Modulation of Aryl Hydrocarbon Receptor-Mediated Activities by Flavonoids. Toxicol Sci. 2018;164(1):205-217.

[4] Yoon K, Chen C-C, Orr AA, Barreto PN, Tamamis P, Safe S. Activation of COUP-TF1 by a Novel Diindolylmethane Derivative. Cells 2019:8;220.

[5] Mohan RR, Wilson M, Gorham RD Jr, Harrison RES, Morikis VA, Kieslich CA, Orr AA, Coley AV, Tamamis P, Morikis D. Virtual Screening of Chemical Compounds for Discovery of Complement C3 Ligands. ACS Omega. 2018;3(6):6427-6438.

[6] Kokotidou C, Jonnalagadda SVR, Orr AA, Apostolidou C, Seoane-Blanco M, Llamas-Saiz AL, Kotzabasaki M, Chatzoudis A, Mossou E, Forsyth VT, Mitchell EP, Bowler MW, van Raaij MJ, Tamamis P, Mitraki A. The GAIIG domain from Amyloid-β and the HIV-1 gp120 V3 loop as a Source of Inspiration for Novel Amyloid Scaffolds and Potential Therapeutics. FEBS Letters 2018:11;1777-1788.