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 inter actions, The method utilizes binding data generated from the analysis of ch imeric proteins with chimeric peptides. To each chimeric part of the peptid e and receptor are assigned descriptors, thus creating a matrix of X descri ptors. These descriptors are then correlated with the experimentally determ ined 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 wi th wild-type MC1 and MC3 receptors, and MC1/MC3 receptor chimeras tin total 40 peptide-receptor combinations. Two types of PLS models could be created , one that revealed the relationships between receptor and peptide structur e and peptide binding pk; values (i.e., affinity) (R-2 and Q(2) being 0.71 and 0.62, respectively), and another that revealed the relationships betwee n peptide and receptor structure and peptide-receptor selectivity (R-2 and Q(2) being 0.64 and 0.57, respectively), After addition of cross-terms thes e models improved significantly; the R-2 and Q(2) being 0.93 and 0.75 for a ffinity, and 0.92 and 0.72 for selectivity, respectively. The analysis show s that the high affinity of the MSH-peptides is primarily achieved by inter actions of the peptides' C-terminal amino acids with TM2 and TM3 of the rec eptor, and, to a lesser extent, by the interaction of the N-terminus with T M1, TM2 and TM3 of the receptor. However, in contrast, the MC1 receptor sel ectivity is primarily determined by an interaction of the peptides' N-termi ni with TM2/3 of the receptor. Moreover, the cross-terms of the PLS model r evealed the existence of a strong interaction between TM6/7 and TM2/3 of th e receptors. (C) 2001 Elsevier Science B.V. All rights reserved.