TY - JOUR
T1 - Amber-Compatible Parametrization Procedure for Peptide-like Compounds
T2 - Application to 1,4-and 1,5-Substituted Triazole-Based Peptidomimetics
AU - Marion, Antoine
AU - Góra, Jerzy
AU - Kracker, Oliver
AU - Fröhr, Tanja
AU - Latajka, Rafaa
AU - Sewald, Norbert
AU - Antes, Iris
N1 - Publisher Copyright:
© 2017 American Chemical Society.
PY - 2018/1/22
Y1 - 2018/1/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040946101&partnerID=8YFLogxK
U2 - 10.1021/acs.jcim.7b00305
DO - 10.1021/acs.jcim.7b00305
M3 - Article
C2 - 29112399
AN - SCOPUS:85040946101
SN - 1549-9596
VL - 58
SP - 90
EP - 110
JO - Journal of Chemical Information and Modeling
JF - Journal of Chemical Information and Modeling
IS - 1
ER -