A helix initiation motif, XLLRA, is stabilized by hydrogen bond, hydrophobic and van der Waals interactions

Five partially overlapping synthetic peptides containing the N-terminal portion of the leucine zipper (LZ)-like domain of human immunodeficiency virus envelope glycoprotein gp41 were used to deduce the helix initiation site. Circular dichroism (CD) data suggested a strong helix-inducing motif, LLRA. The coupling constant and nuclear Overhauser effect (NOE) results obtained from nuclear magnetic resonance experiments in 20% trifluoroethanol aqueous solution at 280 K for the four decapeptides under study suggested that the motif XLLRA, where X is a group or an amino acid residue capable of forming hydrogen bond to arginine, constitutes a helix nucleation core. A similar conclusion was reached for a pentadecapeptide in water, suggesting that the result was not dependent on both chain length and the helix promoting medium. Detailed analysis of NOE and CD data from the four decapeptides indicated that the acetyl group and asparagine had a strong tendency to be helix N-capping, in confirmation of previous studies. Molecular modeling using restraints derived from NOE data showed that van der Waals, hydrophobic interactions and hydrogen bonds contribute synergetically to the stability of the core structure. The concept of nucleation core consisting of a few amino acids may be generally applied in proton design and folding studies.