A tunable coarse-grained model for ligand-receptor interaction

PLoS Comput Biol. 2013;9(11):e1003274. doi: 10.1371/journal.pcbi.1003274. Epub 2013 Nov 14.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology / methods
  • Computer Simulation
  • Ligands*
  • Models, Molecular*
  • Protein Binding*
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / metabolism*

Substances

  • Ligands
  • Receptors, Cell Surface

Grants and funding

This work has been supported by the Ministry of Science and Technology of Spain via a Ramon Y Cajal Fellowship (Ref. RYC-2010-07450) and a Project from Plan Nacional framework (Ref. BFU2011-30303), and a Marie Curie International Reintegration Grant from the EU (Ref. 248346-NMSSBLS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.