Folding and binding energy of a calmodulin-binding cell antiproliferative peptide

• We simulate variants of a peptide that was shown to reduce cell proliferation.
• The binding site on calmodulin is engaged via a phenylalanine anchor.
• The shorter variant, though intrinsically disordered, achieves better binding.
• A hydrophobic co-anchoring residue optimizes binding.

We carry out a computational study of a calmodulin-binding peptide shown to be effective in reducing cell proliferation. We find several folded states for two short variants of different length of the peptide and determine the location of the binding site on calmodulin, the binding free energy for the different conformers and structural details that play a role in optimal binding. Binding to a hydrophobic pocket in calmodulin occurs via an anchoring phenylalanine residue of the natively disordered peptide, and is enhanced when a neighbouring hydrophobic residue acts as a co-anchor. The shorter sequence possesses better binding to calmodulin, which is encouraging in terms of the development of non-peptide analogues as therapeutic agents.

Figure optionsDownload high-quality image (282 K)Download as PowerPoint slide