A tunable coarse-grained model for ligand-receptor interaction

• Published in: PLoS computational biology Vol. 9; no. 11; p. e1003274
• Main Authors: Ruiz-Herrero, Teresa, Estrada, Javier, Guantes, Raúl, Miguez, David G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01-11-2013; Public Library of Science (PLoS)
• Subjects: Binding sites (Biochemistry); Computational biology; Computational Biology - methods; Computer Simulation; Diffusion; Kinetics; Ligands; Ligands (Biochemistry); Models, Molecular; Physiological aspects; Protein Binding; Receptors, Cell Surface - chemistry; Receptors, Cell Surface - metabolism; Software; Statistical analysis; Spain; Models, Molecular; Protein Binding; Ligands; Receptors, Cell Surface; Computer Simulation; Computational Biology
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1003274

Cell-surface receptors are the most common target for therapeutic drugs. The design and optimization of next generation synthetic drugs require a detailed understanding of the interaction with their corresponding receptors. Mathematical approximations to study ligand-receptor systems based on reaction kinetics strongly simplify the spatial constraints of the interaction, while full atomistic ligand-receptor models do not allow for a statistical many-particle analysis, due to their high computational requirements. Here we present a generic coarse-grained model for ligand-receptor systems that accounts for the essential spatial characteristics of the interaction, while allowing statistical analysis. The model captures the main features of ligand-receptor kinetics, such as diffusion dependence of affinity and dissociation rates. Our model is used to characterize chimeric compounds, designed to take advantage of the receptor over-expression phenotype of certain diseases to selectively target unhealthy cells. Molecular dynamics simulations of chimeric ligands are used to study how selectivity can be optimized based on receptor abundance, ligand-receptor affinity and length of the linker between both ligand subunits. Overall, this coarse-grained model is a useful approximation in the study of systems with complex ligand-receptor interactions or spatial constraints.