PTM-Psi: A Python Package to Facilitate the Computational Investigation of Post-Translational Modification on Protein Structures and Their Impacts on Dynamics and Functions*

Protein post-translational modification (PTM) occurs after a protein has been synthesized from its genetic template and involves chemical changes to its specific amino acid residues. Despite the central role of PTM in regulating molecular interactions, particularly those driven by reversible redox reactions, it remains difficult to interpret PTMs in terms of protein dynamics and function because there are many combinatorially enormous methods to modify the amino acids in response to changes in proteins’ 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 from an inferred or experimentally determined protein structure. The tool is a Python-based workflow, PTM-Psi, that integrates several established open-source software packages, thereby enabling a user to infer structure from sequences, develop force fields for non-standard amino acids using quantum mechanics, calculate free energy perturbations by molecular dynamics simulations, and score the bound complexes by docking algorithms. Using the S-nitrosylation of several cysteines on the GAP2 protein as an example, we demonstrated the utility of PTM-Psi that aids the interpretation of the sequence-structure-function relationship on the data from thiol redox proteomics. We showed that S-nitrosylated cysteine exposed to the solvent indirectly influences 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 responsive to redox environmental changes and lays the foundation for automation that will be useful for modeling molecular and systems biology.