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

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journal contribution
posted on 02.01.2017, 00:00 by Joseph A. Morrone, Alberto Perez, Qiaolin Deng, Sookhee N. Ha, M. Katharine Holloway, Tomi K. Sawyer, Bradley S. Sherborne, Frank K. Brown, Ken A. Dill
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.