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

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• 作者：Joseph A. MorroneAlberto Perez ; Qiaolin Deng ; Sookhee N. Ha ; M. Katharine Holloway ; Tomi K. Sawyer ; Bradley S. Sherborne ; Frank K. Brown ; Ken A. Dill
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2017
• 出版时间：February 14, 2017
• 年：2017
• 卷：13
• 期：2
• 页码：863-869
• 全文大小：358K
• ISSN：1549-9626

文摘

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.