Modeling of the Amino Acid Side Chain Effects on Peptide Conformation

Semiempirical AM1 calculations were carried out for quantum-chemically optimized minimum energy conformations of peptides (Ala)4-X-(Ala)4, where X stands for different l-α-amino acids (Ala, Arg, Asn, Asp, Cys, Gln, Glu, Gly, His, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val). The effect of these variable amino acids on the conformation of the model peptide was quantified in terms of the conformational “strain energy” (ΔHstrain), and also analyzed in terms of spatial compatibility of the peptides. The ΔHstrain corresponds to the energy of transformation from the minimum conformation of the alanine-containing peptide into the conformation, optimized for the X-containing peptide. The results of calculations revealed that variation of the amino acid X influences the conformation of the model peptide and determines the value of the “strain effect.” As the ΔHstrain values characterize interaction between the amino acid side group and the surrounding peptide fragment, an attempt was made to derive a set of parameters that would quantify the influence of a single amino acid on the conformation of a peptide/protein molecule. These parameters could be used as structure-dependent molecular descriptors in developing the quantitative structure-activity relationships for peptides.