A Curvilinear-Path Umbrella Sampling Approach to Characterizing the Glue-like Mechanism of Rapamycin-Analogs

Dhananjay Joshi^1*, Jung-Hsin Lin^1,2,3,4,5

¹Research Center for Applied Science, Academia Sinica, Taipei, Taiwan
²Biomedical Translation Research Center, National Biotechnology Research Park, Academia Sinica, Taipei, Taiwan
³Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
⁴School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
⁵College of Engineering Sciences, Chang Gung University, Taoyuan, Taiwan

* Presenter:Dhananjay Joshi, email:joshid@gate.sinica.edu.tw

We apply the curvilinear-path umbrella sampling simulation approach to characterize the protein–ligand interaction energetics of FKBP12-rapamycin binary complex and explore the molecular glue-like mechanism of the rapamycin analogs (rapalogs) in a protein-ligand-protein ternary complex. First, the binding free energies between rapamycin and FKBP12^WT along with its two variants, FKBP12^D37V and FKBP12^Y82F, are estimated. The calculated standard free energies of binding for the binary systems agree well with the experimental data. Next, this approach is further extended to explore the role of rapalogs in forming FKBP12-rapalogs-FRB ternary complex. Interestingly, the simulations of the dissociation reaction of FKBP12-rapamycin-FRB exhibited a tug-of-war behavior between FRBP12 and FRB to bind with the rapamycin analogs, which reveals that rapalogs prefers to bind with FKBP12 more than with FRB. Thus, these glue-like molecules rapalogs are anticipated to follow a step-wise path of first forming FKBP12-rapamycin complex and then the ternary complex with FRB.

Keywords: Umbrella Sampling Simulations, Molecular dynamics simulations, Free Energy calculation, Protein-ligand interactions, Computational Biophysics