(738g) Computational Screening of Photoactive Cyclic Peptides for Self Assembly and Disassembly

Cyclic peptides have been widely studied for applications such as targeted therapeutics [1] and biologically compatible nanostructures [2]. The ability to control the assembly of peptide nanostructures in vivo is of interest for applications such as targeted drug delivery. We introduce the potential for photoactive assembly and disassembly to cyclic peptides by adding azobenzene linkers. Azobenzene undergoes a reversible photoinduced transition between an extended trans ground state configuration and a compact cis exited state configuration [3]. We seek cyclic azobenzene-peptide sequences that assemble when the azobenzene linker is in the trans configuration and disassemble when azobenzene linker is in the cis configuration.

The large potential parameter space for amino acid sequences makes experimental screening cumbersome. We computationally screened cyclic azobenzene-peptide sequences by computing dimer binding free energies for azobenzene-peptide sequences using well-tempered metadynamics [4]. The peptide portion is modeled using the CHARMM 36 force field. Modeling the azobenzene linker required the development of a new force field. We use the CHARMM general force field [5] to fit parameters for the ground state trans azobenzene linker and the exited state cis azobenzene linker. Separate simulations for the dimer binding free energy with trans and cis azobenzene are performed. Peptide sequences of varying length, side chain size, and side chain hydrophobicity are screened to find dimers that are stable when the azobenzene linker is in the trans configuration, and unstable with the azobenzene linker in the cis configuration.

References

[1] A. Tapeinou, M-T Matsoukas, C. Simal, T. Tselios, Biopolymers, 2015, 104, 453â??461.

[2] D. Mandal, A. N. Shirazi, K. Parang, Org. Biomol. Chem., 2014, 12, 3544-3561.

[3] C. Renner, L. Moroder, ChemBioChem, 2006, 7, 868-878.

[4] A. Barducci, G. Bussi, M. Parrinello, Phys. Rev. Lett., 2008, 100, 020603.

[5] K. Vanommeslaeghe et al., J. Comp. Chem., 2010, 31, 671-690.