1 research outputs found
Amber-Compatible Parametrization Procedure for Peptide-like Compounds: Application to 1,4- and 1,5-Substituted Triazole-Based Peptidomimetics
Peptidomimetics
are molecules of particular interest in the context
of drug design and development. They are proteolytically and metabolically
more stable than their natural peptide counterparts but still offer
high specificity toward their biological targets. In recent years,
1,4- and 1,5-disubstituted 1,2,3-triazole-based peptidomimetics have
emerged as promising lead compounds for the design of various inhibitory
and tumor-targeting molecules as well as for the synthesis of peptide
analogues. The growing popularity of triazole-based peptidomimetics
and a constantly broadening range of their application generated a
demand for elaborate theoretical investigations by classical molecular
dynamics simulations and molecular docking. Despite this rising interest,
accurate and coherent force field parameters for triazole-based peptidomimetics
are still lacking. Here, we report the first complete set of parameters
dedicated to this group of compounds, named TZLff. This parametrization
is compatible with the latest version of the AMBER force field (ff14SB)
and can be readily applied for the modeling of pure triazole-based
peptidomimetics as well as natural peptide sequences containing one
or more triazole-based modifications in their backbone. The parameters
were optimized to reproduce HF/6-31G* electrostatic potentials as
well as MP2/cc-pVTZ equilibrium Hessian matrices and conformational
potential energy surfaces through the use of a genetic algorithm-based
search and least-squares fitting. Following the standards of AMBER,
we introduce residue building units, thus allowing the user to define
any given sequence of triazole-based peptidomimetics. Validation of
the parameter set against ab initio- and NMR-based reference systems
shows that we obtain fairly accurate results, which properly capture
the conformational features of triazole-based peptidomimetics. The
successful and efficient parametrization strategy developed in this
work is general enough to be applied in a straightforward manner for
parametrization of other peptidomimetics and, potentially, any polymeric
assemblies