Molecular Simulations Identify Binding Poses and Approximate Affinities of Stapled α‑Helical Peptides to MDM2 and MDMX

• Published in: Journal of chemical theory and computation Vol. 13; no. 2; pp. 863 - 869
• Main Authors: Morrone, Joseph A, Perez, Alberto, Deng, Qiaolin, Ha, Sookhee N, Holloway, M. Katharine, Sawyer, Tomi K, Sherborne, Bradley S, Brown, Frank K, Dill, Ken A
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14-02-2017
• ISSN: 1549-9618; 1549-9626
• DOI: 10.1021/acs.jctc.6b00978

Traditionally, computing the binding affinities of proteins to even relatively small and rigid ligands by free-energy methods has been challenging due to large computational costs and significant errors. Here, we apply a new molecular simulation acceleration method called MELD (Modeling by Employing Limited Data) to study the binding of stapled α-helical peptides to the MDM2 and MDMX proteins. We employ free-energy-based molecular dynamics simulations (MELD-MD) to identify binding poses and calculate binding affinities. Even though stapled peptides are larger and more complex than most protein ligands, the MELD-MD simulations can identify relevant binding poses and compute relative binding affinities. MELD-MD appears to be a promising method for computing the binding properties of peptide ligands with proteins.