Sequences of human proteins are frequently prepared as synthetic oligopeptides to assess their functional ability to act as compounds modulating pathways involving the parent protein. Our objective was to analyze a set of oligopeptides, to determine if their solubility or activity correlated with features of their primary sequence, or with features of properties inferred from three-dimensional structural models derived by conformational searches. We generated a conformational database for a set of 78 oligopeptides, derived from human proteins, and correlated their 3D structures with solubility and biological assay activity (as measured by platelet activation and inhibition). Parameters of these conformers (frequency of coil, frequency of turns, the degree of packing, and the energy) did not correlate with solubility, which was instead partly predicted by two measures obtained from primary sequence analysis, that is, the hydrophobic moment and the number of charges. The platelet activity of peptides was correlated with a parameter derived from the structural modeling; this was the second virial coefficient (a measure of the tendency for a structure to autoaggregate). This could be explained by an excess among the active peptides of those which had either a large number of positive charges or in some cases a large number of negative charges, with a corresponding deficit of peptides with a mixture of negative and positive charges. We subsequently determined that a panel of 523 commercially available (and biologically active) peptides shared this elevation of absolute net charge: there were significantly lower frequencies of peptides of mixed charges compared to expectations. We conclude that the design of biologically active peptides should consider favoring those with a higher absolute net charge.
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