How Does the Recently Discovered Peptide MIP Exhibit Much Higher Binding Affinity than an Anticancer Protein p53 for an Oncoprotein MDM2?
Abstrak
An oncoprotein MDM2 binds to the extreme N-terminal peptide region of a tumor suppressor protein p53 (p53NTD) and inhibits its anticancer activity. We recently discovered a peptide named MIP which exhibits much higher binding affinity for MDM2 than p53NTD. Experiments showed that the binding free energy (BFE) of MDM2-MIP is lower than that of MDM2-p53NTD by ~-4 kcal/mol. Here we develop a theoretical method which is successful in reproducing this quantitative difference and elucidating its physical origins. It enables us to decompose the BFE into a variety of energetic and entropic components, evaluate their relative magnitudes, and identify the physical factors driving or opposing the binding. It should be applicable also to the assessment of differences among ligands in the binding affinity for a particular receptor, which is a central issue in modern chemistry. In the MDM2 case, the higher affinity of MIP is ascribed to a larger gain of translational, configurational entropy of water upon binding. This result is useful to the design of a peptide possessing even higher affinity for MDM2 as a reliable drug against a cancer.
Topik & Kata Kunci
Penulis (9)
Tatsuya Yamada
Tomohiko Hayashi
Simon Hikiri
N. Kobayashi
H. Yanagawa
M. Ikeguchi
M. Katahira
T. Nagata
M. Kinoshita
Format Sitasi
Akses Cepat
- Tahun Terbit
- 2019
- Bahasa
- en
- Total Sitasi
- 13×
- Sumber Database
- Semantic Scholar
- DOI
- 10.1021/acs.jcim.9b00226
- Akses
- Open Access ✓