Molecular level understanding of the functionality of PDZ3 variants via advanced all-atom simulations and dynamic residue network analyses

Official URL: https://risc01.sabanciuniv.edu/record=b2583879_(Table of contents)

The third PDZ domain of PSD-95 (PDZ3) constitutes a common model to study single domain allostery without significant structural changes. In PDZ3, H372 directly connected to the binding site and G330 holding an off-binding-site position, were designated to assess the effect of mutations on binding selectivity. It has been observed that the H372A and G330T-H372A mutations change ligand preferences from class I (T/S amino acid at position -2 of the ligand) to class II (hydrophobic amino acid at the same position). Alternatively, the G330T single mutation leads to the recognition of both ligand classes. We have performed a series of molecular dynamics (MD) simulations for previously mentioned PDZ3 variants in the absence and presence of both types of ligands. With the combination of free energy difference calculations and a detailed analysis of MD trajectories, binding behavior of PDZ3 mutants, as well as their effects on ligand selection and binding affinities are explained. To scrutinize the residue-by-residue interaction we employ graph theory, and we assess dynamical community composition by using Girvan-Newman algorithm. We find that the highly charged and distal N-terminus share the same community with the ligand in the functional complexes. N- and C-termini of PDZ3 share communities, and α3 acts as a hub for the whole protein by sustaining the communication with all structural segments. Thus, ligand binding fate in PDZ3 is traced to the population of community compositions extracted from dynamics despite the lack of significant conformational changes.