Forcefield_PTM

Forcefield_PTM provides self-consistent AMBER forcefield parameters for 32 common post-translational modifications (PTMs) to enable accurate molecular dynamics simulations compatible with the ff03 parameter set.

Key Features:

• Scope and compatibility: Parameter set covers 32 common PTMs and is built on and compatible with the AMBER ff03 parameter set for consistent molecular dynamics simulations.
• Partial charge derivation: Partial charges were determined using ab initio calculations followed by a two-stage RESP-fitting procedure in an ether-like implicit solvent.
• Charge validation: Derived partial charges show consistency with previously reported values for phosphorylated amino acids and trimethyllysine obtained using different parameterization methods.
• Structural dataset: Parameters were derived from a curated Protein Data Bank (PDB) dataset including single and multiple PTMs in modified and unmodified structures to assess background structural similarities across secondary and tertiary contexts.
• Macroscopic validation: Extensive macroscopic testing used unrestrained all-atom Langevin molecular dynamics simulations in the AMBER framework in implicit solvent for 34 systems (17 modified/unmodified pairs) evaluating secondary structure preservation, energy stability, and trajectory correlations.
• Microscopic validation and tuning: Microscopic comparisons between quantum mechanical and AMBER single point energies across key χ torsions for several PTMs were used to adjust parameters by minimizing mean squared errors and maximizing squared correlation coefficients.

Scientific Applications:

• Protein structure prediction: Use of PTM-specific forcefield parameters to model modified residues in structural prediction workflows.
• Peptide design: Application of parameterized PTMs in peptide design studies involving modified side chains.
• Molecular docking: Incorporation of modified residue parameters in docking studies to account for PTM-induced changes in interactions.
• PTM effects on folding and dynamics: Investigation of how specific PTMs influence protein folding, stability, and dynamic behavior.
• Comparative structural analysis: Example application comparing phosphorylated versus dephosphorylated forms of OdhI to assess PTM-driven structural differences.

Methodology:

Ab initio calculations, two-stage RESP-fitting in an ether-like implicit solvent, curation of PDB structures with single and multiple PTMs, unrestrained all-atom Langevin MD simulations in AMBER implicit solvent for 34 systems (17 pairs), and quantum mechanical versus AMBER single-point energy comparisons across key χ torsions with parameter adjustments minimizing mean squared error and maximizing squared correlation coefficients.