Conformational study of N-methylated alanine peptides and design of A<img src='/image/spc_char/beta.gif' border=0> inhibitor

Abstract

N-Methylation increases the proteolytic stability of peptides and leads to improved pharmacological and increased nematicidal property against plant pathogens. In this study, the quantum mechanical and molecular dynamic simulation approaches were used to investigate conformational behavior of peptides containing only N-methylated alanine (NMeAla) residues and N-methylated alanine and alanine residues at alternate positions. <span style="color:black;mso-ansi-language: DE" lang="DE">The amide bond geometry was found to be <i style="mso-bidi-font-style:normal">trans </i>and the poly NMeAla peptides were shown to populate in the helical structure without hydrogen bond with <img src='http://www.niscair.res.in/jinfo/image2.gif' border=0>, <img src='http://www.niscair.res.in/jinfo/image3.gif' border=0> values of ~ 0, 90˚ stabilized by carbonyl-carbonyl interactions. Molecular dynamic simulations in water/methanol revealed the formation of β-strand structure, irrespective of the starting geometry due to the interaction of solvent molecules with the carbonyl groups of peptide backbone. Analysis of simulation results as a function of time suggested that the opening of helical structure without hydrogen bond started from C-terminal. Conformational behavior of peptides containing N-MeAla and Ala was used to design <span style="color:black;mso-ansi-language: DE" lang="DE">A<span style="font-family:Symbol;mso-ascii-font-family:" times="" new="" roman";="" mso-hansi-font-family:"times="" roman";color:black;mso-ansi-language:de;="" mso-char-type:symbol;mso-symbol-font-family:symbol"="" lang="DE">b<span style="color:black;mso-ansi-language:DE" lang="DE"> peptide inhibitor <span style="color:black; mso-ansi-language:DE" lang="DE">and the model tetrapeptide Ac-Ala-NMeAla-Ala-NHMe in the β-strand structure was shown to interact with the hydrophobic stretch of Aβ15-42 peptide.

</span></span></span></span></span></span></span></span></span>