A consistent S-Adenosylmethionine force field improved by dynamic Hirshfeld-I atomic charges for biomolecular simulation

Abstract

S-Adenosylmethionine (AdoMet) is involved in many biological processes as cofactor in enzymes transferring its sulfonium methyl group to various substrates. Additionally, it is used as drug and nutritional supplement to reduce the pain in osteoarthritis and against depression. Due to the biological relevance of AdoMet it has been part of various computational simulation studies and will also be in the future. However, to our knowledge no rigorous force field parameter development for its simulation in biological systems has been reported. Here, we use electronic structure calculations combined with molecular dynamics simulations in explicit solvent to develop force field parameters compatible with the AMBER99 force field. Additionally, we propose new dynamic Hirshfeld-I atomic charges which are derived from the polarized electron density of AdoMet in aqueous solution to describe its electrostatic interactions in biological systems. The validation of the force field parameters and the atomic charges is performed against experimental interproton NOE distances of AdoMet in aqueous solution and crystal structures of AdoMet in the cavity of three representative proteins.

Improved NOE fitting for flexible molecules based on molecular mechanics data – a case study with S-adenosylmethionine

“…A recent NMR study by Markham et al 23 added further NOESY and ROESY information regarding interproton distances, which similarly found the anti-3'-endo conformation dominated. Such interproton distances derived from NOE (Nuclear Overhauser Enhancement) experiments can be used as part of evaluations of the quality of molecular force fields 26 where they introduced and improved the SAM force field for molecular simulations with a better description of involved conformers. However, when dealing with simulation averages of molecules representing a mixture of two or more conformers in equilibrium, the comparison with NMR data comes with significant challenges.…”

Restriction of S-adenosylmethionine conformational freedom by knotted protein binding sites

“…To investigate the conformations of SAM in its free form, we performed 1 µs long simulation of SAM in water using AMBER99 force field with improved parameters for the ligand [31]. Principal Component Analysis (PCA) of the trajectory shows that the rotation around the glycosidic angle has the biggest contribution to the ligand’s flexibility as it interchanges between syn and anti conformations.…”

“…Molecular Dynamics (MD) simulations of a free ligand in solvent was done using GROMACS 5.0.2 [40] package and AMBER99 force field [41] with improved parameters for the ligand [31]. The simulation was done for 1 µs in constant temperature (298K) and pressure (1 atm) with 150 mM of NaCl present.…”

Conformational sampling and polarization of Asp26 in pKa calculations of thioredoxin

“…31 Recently, we have shown that they are also suitable for condensed phases reproducing partition coefficients of DNA bases and hydration free energies of 613 organic molecules in the FreeSolv database. 28,30 Because the molecular environment alters the molecular electron density of ionizable residues and these variations may depend on the protein conformation we employ our recently proposed dynamic method, [25][26][27]29 which describes the molecular environment provided by the protein and the solvent explicitly in QM/MM calculation to derive the polarized electron density from which the average atomic charges are derived. In contrast to the approach of Kamerlin 24 discussed above, QM/MM is only used to obtain atomic charges on single representative conformations from force field based molecular dynamics simulations.…”