Force-field parametrization of retro-inverso modified residues: Development of torsional and electrostatic parameters

Abstract

Torsional and the electrostatic parameters for molecular mechanics studies of retro-inverso modified peptides have been developed using quantum mechanical calculations. The resulting parameters have been compared with those calculated for conventional peptides. Rotational profiles, which were obtained spanning the corresponding dihedral angle, were corrected by removing the energy contributions associated to changes in interactions different from torsion under study. For this purpose, the torsional energy associated to each point of the profiles was estimated as the corresponding quantum mechanical energy minus the bonding and nonbonding energy contributions produced by the perturbations that the variation of the spanned dihedral angle causes in the bond distances, bond angles and the other dihedral angles. These energies were calculated using force-field expressions. The corrected profiles were fitted to a three-term Fourier expansion to derive the torsional parameters. Atomic charges for retro-inverso modified residues were derived from the rigorously calculated quantum mechanical electrostatic potential. Furthermore, the reliability of electrostatic models based on geometry-dependent charges and fixed charges has been examined.

Peptide and protein mimetics by retro and retroinverso analogs

“…It was also found that retro and retroinverso analogs have a stronger helical propensity and they cannot mimic the original peptide due to the reversal of side chain and backbone. Such detailed molecular dynamics studies can provide a lead for development of a modified retroinverso analog that can mimic the original (Curcó, Rodríguez‐Ropero, & Alemán, ). If a retroinverso analog does not work then its structure based rational modifications can make it work or sometimes even improve upon retroinverso analog and original peptide activity (Nieddu et al., ).…”

“…Substitution of Phe171 and Val173 (which forms the binding site for HSP70) with more hydrophobic unusual amino acids improved peptide antiviral activity (Khachatoorian et al., ). Cyclized retroinverso analog of a peptide corresponding to dimerization domain of EGF receptor (242–259) is able to block the dimerization of EGF receptor and consequently suppress proliferation of A431 cancer cells (Curcó et al., ; Mizuguchi et al., ). Cyclization here is necessary because, in original EGF receptor, this sequence (242–259) makes a hairpin turn, which is otherwise not possible in a small peptide.…”

Parameterization of the torsional potential for calix[4]arene‐substituted poly(thiophene)s

“…It is worth noting that in these compounds, the importance of the E per values should be attributed not only to the nonbonding contribution, which is typically found to be the most significant in the torsional parameterization of (bio)organic compounds, 23,24,48,49 but also to the stretching and bending energy terms. Thus, the geometric parameters of oligothiophenes, especially the inter-ring bond lengths and angles, vary with the degree of p-p conjugation, which changes drastically upon rotating the dihedral angle h.…”

“…As can be seen, the shape of the E per profiles is completely different from the E QM ones, especially for the bTph, which has been also included in Figure 3 for comparison. It is worth noting that in these compounds, the importance of the E per values should be attributed not only to the nonbonding contribution, which is typically found to be the most significant in the torsional parameterization of (bio)organic compounds, 23,24,48,49 but also to the stretching and bending energy terms. Thus, the geometric parameters of oligothiophenes, especially the inter-ring bond lengths and angles, vary with the degree of p-p conjugation, which changes drastically upon rotating the dihedral angle h. [9][10][11][12] The potential energy profiles obtained using the DP1, DP2, and DP3 torsional parameters are relatively similar.…”

“…22 The strategy used to obtain the parameters is based on an early developed procedure, 23 which was recently extrapolated and adapted to complex organic molecules. 24 The reliability of the resulting parameters has been demonstrated by calculating the Potentials of Mean Force (PMFs) of small model molecules in both the gas-phase and chloroform solution through the umbrella sampling methodology. Furthermore, these parameters have been also used to evaluate the structural characteristic of a PT-c4a1 chain in tetrahydrofuran through MD simulations.…”