A CHARMM-Compatible Force Field for N- and Aplha-Methylated Peptides with (Phi,Psi) Energy Correction Grid

Abstract

Synthetic peptides are a convenient avenue for biomedical applications such as the design of drugs in which natural peptides and key motifs from proteins are rigidified and metabolically stabilized.[1][2] As the relative flexibility of peptides often encumbers the experimental study of their structure, they are an attractive target for Molecular Dynamics computational studies. However, since they exhibit similar subtle sequence-structure relationships as natural proteins, their study requires an empirical force field with a similar level of refinement as protein force fields such as CHARMM36.[3] While nonstandard side chains can often directly be studied with existing protein force fields, and the study of D-amino acids is straightforwardly enabled by constructing a mirror-image potential, backbone modifications invalidate dihedral force field terms associated with the (Phi,Psi) conformational energy surface. Within the framework of the CHARMM36 force field, we present the parametrization of N- and alpha-methylated amino acids, two staples in the peptide chemist's arsenal for increasing peptides’ metabolic stability and secondary structure rigidity.[4][5] This effort includes the construction of dedicated CMAP cross terms, which consist of a 2D grid of energy corrections in (Phi,Psi) space. The resulting parameter set is validated against experimental data on relevant peptides. 1. V. J. Hruby, P. M. Balse, Curr. Med. Chem. 2000, 7, 945-970. 2. C. Adessi, C. Soto, Curr. Med. Chem. 2002, 9, 963-978. 3. R. Best, X. Zhu et al., J. Chem. Theory Comput. 2012, 8, 3257-3273. 4. J. Chatterjee, C. Gilon et al., Acc. Chem. Res. 2008, 41, 1331-1342. 5. R. Gratias, R. Konat et al., J. Am. Chem. Soc. 1998, 120, 4763-4770.