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Classical molecular dynamics and metadynamics simulations decipher the mechanism of CBP30 selectively inhibiting
Qianqian Wang1, Xiaoli An, Jiahui Xu
1State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau, China. lliu@must.edu.mo lhleung@must.edu.mo xjyao@must.edu.mo.
Abstract:
The selective modulation of individual bromodomains (BDs) by small molecules represents an important strategy for the treatment of various cancers, considering that the BD-containing proteins share common BD structures and distinct pharmacological functions. Small molecule inhibitors targeting BDs outside of the bromodomain and extraterminal domain (BET, including BRD2-4 and BRDT) family are particularly lacking. CBP30 exhibited excellent selectivity for the transcriptional coactivators CBP (CREB binding protein) and p300 bromodomains, providing a new opportunity for designing selective non-BET inhibitors. Here, we performed classical molecular dynamics (cMD) and metadynamics simulations to reveal the selective mechanism of CBP30 binding with CBP/p300 and BRD4-BD1/BD2 bromodomains. The cMD simulations combined with binding free energy calculations were performed to compare the overall features of CBP30 binding with CBP/p300 and BRD4-BD1/BD2 bromodomains. Arg1173/1137, as the unique residue for CBP/p300, was responsible for the selective binding to CBP30 via cation-π and hydrogen bond interactions. Metadynamics simulation, together with unbinding free energy profiles, suggested that the dissociation pathways of CBP30 from CBP/p300 and BRD4-BD1/BD2 bromodomains were different, with the unbinding of the former being more difficult. These findings will be helpful for novel CBP/p300-inhibitor design and rational structural modification of existing inhibitors to increase their selectivity.
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