A Tunable Coarse-Grained Model for Ligand-Receptor Interaction

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.Author Summary: The current importance of cell surface receptors as primary targets for drug treatment explains the increasing interest in a mathematical and quantitative description of the process of ligand-receptor interaction. Recently, a new generation of synthetic chimeric ligands has been developed to selectively target unhealthy cells, without harming healthy tissue. To understand these and other types of complex ligand-receptor systems, conventional chemical interaction models often rely on simplifications and assumptions about the spatial characteristics of the system, while full atomistic molecular dynamics simulations are too computationally demanding to perform many particle statistical analysis. In this paper, we describe a novel approach to model the interaction between ligands and receptors based on a coarse grained approximation that includes explicitly both spatial and kinetic details of the interaction, while allowing many-particle simulations and therefore, statistical analysis at biologically relevant time scales. The model is used to study the binding properties of generic chimeric ligands to understand how cell specificity is achieved, its dependence on receptor concentration and the influence of the distance between subunits of the chimera. Overall, this approach proves optimal to study other ligand-receptor systems with complex spatial regulation, such as receptor clustering, multimerization and multivalent asymmetric ligand binding.