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

[Display omitted] •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....

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Bibliographic Details
Published in:Journal of molecular graphics & modelling 2015-09, Vol.61, p.281-289
Main Authors: Almudallal, Ahmad M., Saika-Voivod, Ivan, Stewart, John M.
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Antineoplastic Agents - chemistry
Antiproliferatives
Binding energy
Binding Sites
Calmodulin
Calmodulin - chemistry
Calmodulin-Binding Proteins - chemistry
Docking
Drug Design
High-Throughput Screening Assays
Humans
Hydrophobic and Hydrophilic Interactions
Ligands
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Sequence Data
Neighbouring
Peptide binding
Peptide modelling
Peptides
Peptides - chemistry
Phenylalanine
Phenylalanine - chemistry
Protein Binding
Protein Structure, Secondary
Protein Structure, Tertiary
Residues
Structure-Activity Relationship
Thermodynamics
User-Computer Interface
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Summary:[Display omitted] •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.
ISSN:1093-3263
1873-4243
DOI:10.1016/j.jmgm.2015.08.002