Development of a Pantetheine Force Field Library for Molecular Modeling

Abstract

Pantetheine is ubiquitous in nature in various forms of pantetheine-containing ligands (PCLs), including coenzyme A and phosphopantetheine. Lack of scalable force field libraries for PCLs has hampered the computational studies of biological macromolecules containing PCLs. We describe here the development of the first generation Pantetheine Force Field (PFF) library that is compatible with Amber force fields; parameterized using Gasteiger, AM1-BCC, or RESP charging methods combined with gaff 2 and f f14SB parameter sets. In addition, a "plug-and-play" strategy was employed to enable the systematic charging of computationally expensive molecules sharing common substructural motifs. The validation studies performed on the PFF library showed promising performance where molecular dynamics (MD) simulations results were compared with experimental data of three representative systems. The PFF library represents the first force field library capable of modeling systems containing PCLs in silico and will aid in various applications including protein engineering and drug discovery.

Decrypting the programming of β-methylation in virginiamycin M biosynthesis

“…Phosphopantetheinyl serine library and force eld parameters 63 were used for AMBER minimisation. The nal representative ensembles correspond to the 20 conformers from each calculation with the lowest restraint energy terms.…”

PyRESP: A Program for Electrostatic Parameterizations of Additive and Induced Dipole Polarizable Force Fields

“…6,7 Additive force fields are also considered to be unable to capture the important cation−π interactions between aromatic rings and charged amino acids, leading to unrealistic receptor− ligand interaction simulations. 8,9 Therefore, a great deal of effort has been directed to developing polarizable models, including the fluctuating charge models, 10,11 the Drude oscillator models, 12−16 and models incorporating induced dipoles 17,18 or continuum dielectric. 19,20 The induced point dipole model is the most studied approach with a long history since the 1970s.…”

“…The importance of modeling polarization effects is well known. For example, during the protein folding process, amino acids forming a hydrophobic core must move from the hydrated environment to the more hydrophobic interior, experiencing considerably different dielectric environments. , Additive force fields are also considered to be unable to capture the important cation−π interactions between aromatic rings and charged amino acids, leading to unrealistic receptor–ligand interaction simulations. , Therefore, a great deal of effort has been directed to developing polarizable models, including the fluctuating charge models, , the Drude oscillator models, − and models incorporating induced dipoles , or continuum dielectric. , …”

“…To date, the computer program RESP has been applied in charge derivations of a variety of additive force fields , and is still being used actively for charge calculations for small organic molecules. ,, Following the idea of charge parameterization by reproducing ESPs, Cieplak et al extended the RESP method for induced dipole electrostatic models, assuming that ESPs around molecules are determined by both permanent charges and atomic-induced dipoles. According to this method, atomic charges are iteratively fitted to the effective ESP, which is the difference between the QM-derived ESPs and the ESPs generated by induced dipoles.…”

Accurate Reproduction of Quantum Mechanical Many-Body Interactions in Peptide Main-Chain Hydrogen-Bonding Oligomers by the Polarizable Gaussian Multipole Model

“…While additive force fields will continue to play important roles, polarizable force fields are expected to extend our ability to study biomolecular systems more adequately due to their ability to model the atomic polarization effects, which are the redistribution of atomic electron density due to the electric field produced by nearby atoms . Polarization effects are important in biological processes such as ligand–receptor interactions, − the interactions of ions with nucleic acids, , the dielectric environmental changes during protein folding, , and enzymatic mechanisms . If more than two atoms are involved, polarization effects lead to nonadditivity, since when polarized by a third atom, any two atoms interact differently from the situation where the third atom is absent.…”