Small, zwitterionic peptides (2-6 residues) are flexible molecules that occur in solution as an ensemble of conformational forms in dynamic equilibrium. They occur widely in Nature as components of the peptide pool produced by protein hydrolysis. Molecular modelling provides information on the conformations they adopt in aqueous solution. Contrary to expectations, they exist in a limited range of conformational forms that arise from particular combinations of backbone torsions. From the computed energies of the conformers, those with similar conformations can be aggregated and a profile of the conformer population displayed using a 3D pseudo- Ramachandran plot. Several different generic peptide transporters have evolved with complementary substrate specificities in response to these varied conformational forms. Molecular recognition templates (MRTs) define the stereo-electronic features of particular conformations that determine peptide recognition and binding by these transporters. The binding and transport of any peptide correlates with the proportion of its conformers that occur in a particular MRT. Specific con former binding appears generally to involve little or no ligand rearrangement, which minimises conformational entropy loss. Conformational analysis of peptide analogues, evaluation of their similarities to normal peptides and comparison of their conformer profiles with MRTs, allows estimates of their molecular recognition as putative bioactive ligands for such proteins, this is illustrated for a variety of pseudopeptides, isosteres and conformationally-constrained analogues. For peptide therapeutics, such as β-lactam antibiotics, inhibitors of angiotensin-converting enzyme, antiviral and chemotherapeutic agents, this approach can be used to evaluate in silico virtual libraries of drug analogues to estimate their potential for targeted delivery and oral availability.
Keywords: Peptides, Molecule Parameters, dipeptide permease, binding protein, isothermal titration calorimetry, tripeptide permease, tripeptide torsional sector, virtual torsion, amino acid
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