ABSTRACT
"There's a time to be born, and a time to die; a time to break down, and a time to build up; a time to weep, and a time to laugh; a time to keep silence, and a time to speak " (Ecclesiastes 3, 2-7). There was a time when automata were designed like clocks. Androids will have the time of their creators, the state of the art in technology, a wealth of experience to draw from, as well as the capacity to carry out actions as being endowed with meaning. The machine will undergo a long period of nurturing, from which it will learn to shape some sort of identity.
ABSTRACT
Peptide T (ASTTTNYT), a segment corresponding to residues 185-192 of gp120, the coat protein of HIV, has several important biological properties in vitro that have stimulated the search for simpler and possibly more active analogs. We have previously shown that pseudocyclic hexapeptide analogs containing the central residues of peptide T retain considerable chemotactic activity. We have now extended the design of this type of analogs to peptides containing different aromatic residues and/or Ser in lieu of Thr. The complex conformation-activity relationship of these analogs called for a reexamination of the basic conformational tendencies of peptide T itself. Here, we present an exhaustive NMR conformational study of peptide T in different media. Peptide T assumes a gamma-turn in aqueous mixtures of ethylene glycol, a type-IV beta-turn conformation in aqueous mixtures of DMF, and a type-II beta-turn conformation in aqueous mixtures of DMSO. The preferred conformations for the analogs were derived from modeling, starting from the preferred conformations of peptide T. The best models derived from the gamma-turn conformation of peptide T are those of peptides XII (DSNYSR), XIII (ETNYTK) and XVI (ESNYSR). The best models derived from the type-IV beta-turn conformation of peptide T are those of peptides XIV (KTTNYE) and XV (DSSNYR). No low-energy models could be derived starting from the type-II beta-turn conformation of peptide T. The analogs with the most favored conformations are also the most active in the chemotactic test.
Subject(s)
Peptide T/chemistry , Peptide T/pharmacology , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Amino Acid Sequence , Cells, Cultured , Chemotaxis, Leukocyte/drug effects , Humans , Models, Molecular , Monocytes/drug effects , Nuclear Magnetic Resonance, Biomolecular , Protein Conformation , Quantum Theory , Structure-Activity RelationshipABSTRACT
CCK-15, a peptide derived from the 115-membered CCK preprohormone, was the object of a comparative conformational analysis by NMR spectroscopy and molecular modeling methods. NMR data in several solvents demonstrate that the propensity of the peptide to fold into a helical conformation is intrinsic, not merely a consequence of the interaction with phosphatidylcholine micelles or with a putative receptor, as suggested by a previous study on CCK-8 (Pellegrini, M.; Mierke, D. Biochemistry 1999, 38, 14775-14783.). The prevailing CCK-15 conformer in a mixture 1,1,1,3,3,3-hexafluoroacetone/water reveals that the residues common to CCK-15 and CCK-8 assume very similar conformations. Our CCK-15 structure is consistent with the model of receptor interaction proposed by Pellegrini and Mierke and discloses possible novel interactions that involve a larger area of the putative receptor. The consensus structure between CCK-15 and CCK-8 shows a good superposition of the side chains of residues 12-14 with crucial moieties of two non-peptidic CCK-A antagonists.
