Predominant torsional forms adopted by oligopeptide conformers in solution: parameters for molecular recognition

Abstract

In this paper, we describe the predominant conformational forms adopted by tripeptides and higher oligopeptides in aqueous solution. About 50 tripeptides and almost 20 higher oligopeptides (4-6 residues) were subjected to conformational analysis using SYBYL Random Search. As with dipeptides (Grail BM, Payne JW. J. Peptide Sci. 2000; 6: 186-199), both tripeptides and higher oligopeptides were found to occupy relatively few combinations of psi-phi space that were distinct from those associated with predominant protein secondary structures (e.g. helices and beta-sheets). Again, the preferred psi (psi) values for the first residue (i - 1) were in sectors encompassed by the ranges from +150 degrees to +/-180 degrees, +60 degrees to +90 degrees and -60 degrees to -90 degrees, which were combined with preferred phi (phi) values for the second residue (i) in sectors with ranges from -150 degrees to +/-180 degrees, -60 degrees to -90 degrees and +30 degrees to +60 degrees. It was notable that tripeptides and, to a greater extent, higher oligopeptides adopted an initial psi (psi) (Tor2) from +150 degrees to +/-180 degrees. For tripeptides, their N-C distances (distance between N-terminal nitrogen and C-terminal carbon atoms) distribute about 6.5 A to give shorter, 'folded' conformers that are similar in length to dipeptides, and longer, 'extended' conformers that are distinct. Furthermore, for higher oligopeptides, their N-C distances did not increment in relation to their increasing number of residues and short, 'folded' conformers were still present. These findings have a bearing upon the recognition of these molecules as substrates for widely distributed peptidases and peptide transporters.

Evaluation of the conformational propensities of peptide isosteres as a basis for selecting bioactive pseudopeptides

“…preferences for both a charged α‐amino‐ and α‐carboxylate terminus, a trans peptide bond and all l ‐stereochemistry, with the nature of the side‐chains being less unimportant (2,3). The precise structural parameters that determine the unique substrate specificities of each of these transporters have recently been established using structure−activity relationships derived from conformational analysis of peptides and assays of substrate transport and binding (6–9). Dpp and Tpp are complementary in recognizing different dipeptide conformations with particular combinations of psi (ψ) and phi (φ) torsions; together they can recognize and transport the bulk of backbone torsional conformations shared by all dipeptides.…”

“…Dpp and Tpp are complementary in recognizing different dipeptide conformations with particular combinations of psi (ψ) and phi (φ) torsions; together they can recognize and transport the bulk of backbone torsional conformations shared by all dipeptides. In addition, each recognizes specific ‘folded conformers’ of tripeptides with ψ i −1 , ω and φ i torsions and α‐amino to α‐carboxylate distance (N‐C) matching those for their respective dipeptide substrates (7–9). Opp is complementary to these transporters in recognizing both ‘elongated tripeptide conformers’ with longer N‐C distances (≥6.5 Å) and ‘elongated conformers’ of higher oligopeptides with specific ψ i −1 and φ i torsions (7,9).…”

“…In addition, each recognizes specific ‘folded conformers’ of tripeptides with ψ i −1 , ω and φ i torsions and α‐amino to α‐carboxylate distance (N‐C) matching those for their respective dipeptide substrates (7–9). Opp is complementary to these transporters in recognizing both ‘elongated tripeptide conformers’ with longer N‐C distances (≥6.5 Å) and ‘elongated conformers’ of higher oligopeptides with specific ψ i −1 and φ i torsions (7,9). These three, archetypal peptide transporters together can handle the predominant conformational forms of di‐, tri‐ and higher oligopeptides found in aqueous solution.…”

“…Molecular recognition templates (MRTs) have been defined that describe the parameters for substrate recognition by each of these generic transporters (7–9). These templates embrace important backbone features, e.g.…”

“…Studies of peptide binding to the purified recognition proteins of Dpp (DppA) and Opp (OppA) have been performed using various techniques such as X‐ray crystallography, isothermal titration calorimetry and radioactive ligand binding (7,8,12–14). Entropy−enthalpy compensation characterizes substrate binding to these peptide transport proteins (8,13,15).…”