PTM‐Psi : A python package to facilitate the computational investigation of p ost‐ t ranslational m odification on p rotein s tructures and their i mpacts on dynamics and functions

Post‐translational modification (PTM) of a protein occurs after it has been synthesized from its genetic template, and involves chemical modifications of the protein's specific amino acid residues. Despite of the central role played by PTM in regulating molecular interactions, particularly those driven by reversible redox reactions, it remains challenging to interpret PTMs in terms of protein dynamics and function because there are numerous combinatorially enormous means for modifying amino acids in response to changes in the protein environment. In this study, we provide a workflow that allows users to interpret how perturbations caused by PTMs affect a protein's properties, dynamics, and interactions with its binding partners based on inferred or experimentally determined protein structure. This Python‐based workflow, called PTM‐Psi, integrates several established open‐source software packages, thereby enabling the user to infer protein structure from sequence, develop force fields for non‐standard amino acids using quantum mechanics, calculate free energy perturbations through molecular dynamics simulations, and score the bound complexes via docking algorithms. Using the S‐nitrosylation of several cysteines on the GAP2 protein as an example, we demonstrated the utility of PTM‐Psi for interpreting sequence–structure–function relationships derived from thiol redox proteomics data. We demonstrate that the S‐nitrosylated cysteine that is exposed to the solvent indirectly affects the catalytic reaction of another buried cysteine over a distance in GAP2 protein through the movement of the two ligands. Our workflow tracks the PTMs on residues that are responsive to changes in the redox environment and lays the foundation for the automation of molecular and systems biology modeling.