A Systematic Framework for Molecular Dynamics Simulations of Protein Post-Translational Modifications

Abstract

By directly affecting structure, dynamics and interaction networks of their targets, post-translational modifications (PTMs) of proteins play a key role in different cellular processes ranging from enzymatic activation to regulation of signal transduction to cell-cycle control. Despite the great importance of understanding how PTMs affect proteins at the atomistic level, a systematic framework for treating post-translationally modified amino acids by molecular dynamics (MD) simulations, a premier high-resolution computational biology tool, has never been developed. Here, we report and validate force field parameters (GROMOS 45a3 and 54a7) required to run and analyze MD simulations of more than 250 different types of enzymatic and non-enzymatic PTMs. The newly developed GROMOS 54a7 parameters in particular exhibit near chemical accuracy in matching experimentally measured hydration free energies (RMSE = 4.2 kJ/mol over the validation set). Using this tool, we quantitatively show that the majority of PTMs greatly alter the hydrophobicity and other physico-chemical properties of target amino acids, with the extent of change in many cases being comparable to the complete range spanned by native amino acids.

Extension and validation of the GROMOS 53A6glyc parameter set for glycoproteins

“…To evaluate whether such difference would provide deficiencies in the N‐glycosidic linkage conformational ensemble during MD simulations, the β‐GlcNAc‐(1→N)‐Asn linkage was studied isolated in solution. Three conditions were considered: (1) using the torsional potential as in GROMOS 45A4, (2) using a single torsional potential, and (3) using three torsional potentials for O5‐C1‐Nδ2‐Cγ, which describes the conformation at 120° as a local minimum. These three potentials were calculated as having phase shifts of 0, 0, and 120, multiplicities of 1, 2, and 2 and force constants of 4.98, 3.90, and −4.69 kJ mol −1 , respectively.…”

Comparative analysis of human and mouse transcriptional cofactors (TcoFs) with special emphasis on intrinsically disordered regions and their associated regulating post‐translational modifications

“…GROMACS have some limitations to parameterize phosphorylated residues in our protein structure. Thus, we amended the Gromos96 54a8 force field using Vienna‐PTM 2.0 program to recognize both phosphorylated and unphosphorylated residues with respect to our work . We added H atoms to our protein and centered in a cubic box by placing at 10 Å distance from the box edge and solvated with water .…”

Extensive Citrullination Promotes Immunogenicity of HSP90 through Protein Unfolding and Exposure of Cryptic Epitopes

“…To derive AMBER-compatible parameters for citrulline, we used an approach outlined in reference (44) that derived GROMOS-compatible parameters by using GLN parameters for the side chain CONH 2 moiety and ARG parameters for the rest of the citrulline atoms. To prepare the HSP90β middle domain simulations, the N- and C-termini of the human HSP90β homology model structure were neutralized using acetamide and N-methylamide patches, respectively.…”