Molecular modeling of bioactive neuropeptides: Substrates of angiotensin I-converting enzyme

Angiotensin I (Ang-I)-converting enzyme (ACE) is a chloride-dependent zinc metallopeptidase that is important in the regulation of cardiovascular functions. In addition to Ang-I and bradykinin, ACE is able to cleave several other peptides, such as neurotensin (NT), substance P, and Angiotensin-(1-7) (Ang-1-7). We have investigated by computational methods the structural and dynamical similarities among these peptides that could be responsible to their molecular recognition by ACE. Conformational and clustering analyses, semiempirical, and density functional theory calculations were performed; in addition, molecular dynamics (MD) simulations of Ang-1-7 both in pure water and in saline conditions were undertaken. Backbones folding pattern between the conformers of each peptide was very similar, mainly sustained by noncovalent interactions, denoting high conservation of the cleavage site. Also, cleavage site showed high folding similarity between the three different substrates and could mean a structural pattern. Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital showed no pattern between the substrates; however, NT-(8-13) HOMO is located at the cleavage site. MD studies showed that Ang-(1-7) has faster relaxation in saline system and less content of intramolecular hydrogen bonds, which could explain the higher cleavage activity of this peptide by ACE in such conditions. (C) 2012 Wiley Periodicals, Inc.