A systematic framework for molecular dynamics simulations of protein post-translational modifications

Area of Science:

• Biochemistry
• Computational Biology
• Structural Biology

Background:

• Post-translational modifications (PTMs) are crucial for protein function, regulating cellular processes.
• Understanding PTMs at an atomistic level is vital but lacks systematic computational tools.
• Molecular dynamics (MD) simulations are premier tools for high-resolution biological analysis.

Purpose of the Study:

• To develop and validate a systematic computational framework for simulating post-translationally modified amino acids using MD.
• To provide force field parameters for over 250 types of enzymatic and non-enzymatic PTMs.
• To quantitatively assess the impact of PTMs on amino acid properties.

Main Methods:

• Development and validation of GROMOS 45a3 and 54a7 force field parameters.
• Running and analyzing molecular dynamics (MD) simulations for over 250 PTM types.
• Validation against experimentally measured hydration free energies.

Main Results:

• Successful development of force field parameters for a wide range of PTMs.
• GROMOS 54a7 parameters achieved near chemical accuracy for hydration free energies (RMSE=4.2 kJ/mol).
• PTMs were shown to significantly alter amino acid hydrophobicity and physico-chemical properties.

Conclusions:

• The developed parameters enable accurate MD simulations of PTMs.
• PTMs induce substantial changes in amino acid properties, comparable to native amino acid diversity.
• This framework advances the atomistic-level understanding of PTMs and their functional consequences.