PNNL

Abstract

Post-translational modification (PTM) of a protein in a living cell refers to the chemical changes on its specific amino acid residues after it has been synthesized from its genetic template. Despite the central role of PTM in regulating molecular interactions, particularly those driven by reversible redox reactions, the interpretation of PTMs on a protein’s dynamics and function remains challenging due to combinatorially enormous ways to modify the amino acids responsive to the changes in its surrounding environment. Here, we develop a new tool that offers knowledge of perturbation by PTM on specific aminio acids for users to intepret how individually or collectively, the PTMs impact a protein’s properties, dynamics, as well as interactions with its binding partners. PTM-Psi, a python-based workflow, integrates several established software packages enabling a user to infer structures from sequencs, to develop force fields for non-standard amino acids using quantum mechanics/molecular mechanics (QM/MM), to compute the free energy perturbation using molecular dynamics simulations (MD), and to score the bound complexes using docking algorithms. Taking the S-nitrosylation on several cysteines of Gap2 protein as an example, we showed that the PTM at the cysteine exposed to solvent influences another one buried at the catalytic site over distance through the connection of the two ligands of Gap2 protein, offering a probable structural interpretation of chemically targeted proteomics data. This tool provides molecularly mechanistic insights into functional regulations not only for cysteines, but also for other types of PTMs responsive to changes in the environment, which can be impactful in modeling synthetic and systems biology.