PLS modeling of chimeric MS04/MSH-peptide and MC₁/MC₃-receptor interactions reveals a novel method for the analysis of ligand-receptor interactions

A novel method has been developed for the analysis of ligand-receptor interactions. The method utilizes binding data generated from the analysis of chimeric proteins with chimeric peptides. To each chimeric part of the peptide and receptor are assigned descriptors, thus creating a matrix of X descriptors. These descriptors are then correlated with the experimentally determined interaction binding affinities for each chimeric receptor/peptide pair by use of partial least-squares projection to latent structures (PLS). The method was applied to analyze the interactions of chimeric MSH-peptides with wild-type MC₁ and MC₃ receptors, and MC₁/MC₃ receptor chimeras (in total 40 peptide-receptor combinations). Two types of PLS models could be created, one that revealed the relationships between receptor and peptide structure and peptide binding pK_i values (i.e., affinity) (R² and Q² being 0.71 and 0.62, respectively), and another that revealed the relationships between peptide and receptor structure and peptide-receptor selectivity (R² and Q² being 0.64 and 0.57, respectively). After addition of cross-terms these models improved significantly; the R² and Q² being 0.93 and 0.75 for affinity, and 0.92 and 0.72 for selectivity, respectively. The analysis shows that the high affinity of the MSH-peptides is primarily achieved by interactions of the peptides' C-terminal amino acids with TM2 and TM3 of the receptor, and, to a lesser extent, by the interaction of the N-terminus with TM1, TM2 and TM3 of the receptor. However, in contrast, the MC₁ receptor selectivity is primarily determined by an interaction of the peptides' N-termini with TM2/3 of the receptor. Moreover, the cross-terms of the PLS model revealed the existence of a strong interaction between TM6/7 and TM2/3 of the receptors.