General principles of binding between cell surface receptors and multi-specific ligands: A computational study

PLoS Comput Biol. 2017 Oct 10;13(10):e1005805. doi: 10.1371/journal.pcbi.1005805. eCollection 2017 Oct.


The interactions between membrane receptors and extracellular ligands control cell-cell and cell-substrate adhesion, and environmental responsiveness by representing the initial steps of cell signaling pathways. These interactions can be spatial-temporally regulated when different extracellular ligands are tethered. The detailed mechanisms of this spatial-temporal regulation, including the competition between distinct ligands with overlapping binding sites and the conformational flexibility in multi-specific ligand assemblies have not been quantitatively evaluated. We present a new coarse-grained model to realistically simulate the binding process between multi-specific ligands and membrane receptors on cell surfaces. The model simplifies each receptor and each binding site in a multi-specific ligand as a rigid body. Different numbers or types of ligands are spatially organized together in the simulation. These designs were used to test the relation between the overall binding of a multi-specific ligand and the affinity of its cognate binding site. When a variety of ligands are exposed to cells expressing different densities of surface receptors, we demonstrated that ligands with reduced affinities have higher specificity to distinguish cells based on the relative concentrations of their receptors. Finally, modification of intramolecular flexibility was shown to play a role in optimizing the binding between receptors and ligands. In summary, our studies bring new insights to the general principles of ligand-receptor interactions. Future applications of our method will pave the way for new strategies to generate next-generation biologics.

MeSH terms

  • Algorithms
  • Binding Sites
  • Computational Biology
  • Ligands*
  • Molecular Dynamics Simulation
  • Monte Carlo Method
  • Protein Binding*
  • Receptors, Cell Surface / chemistry*
  • Receptors, Cell Surface / metabolism*


  • Ligands
  • Receptors, Cell Surface