Conformational dynamics of pantothenate kinase 3 via multiscale simulation

Abstract

Pantothenate-kinase-associated neurodegeneration (PKAN), previously known as Hallervorden- Spatz syndrome, is a rare autosomal recessive disorder characterized by distinctive clinical symptoms. It represents the most prevalent form of neurodegeneration associated with brain iron accumulation (NBIA), accounting for approximately 50% of NBIA cases. PKAN is caused by mutations in the PANK2 gene, resulting in impaired conversion of pantothenic acid (vitamin B5) to coenzyme A (CoA), a vital cofactor in various cellular metabolic pathways. In this study, we employed Gaussian accelerated molecular dynamics (GaMD) simulations and various analytical techniques to investigate the structural dynamics and functional implications of PANK3, a key enzyme associated with PKAN. We utilized crystal structures obtained from the Protein Data Bank (PDB) to simulate both apo (ligand-free) and complexed forms of PANK3, followed by extensive analyses of protein-ligand interactions, structural fluctuations, solvent accessibility, and protein compactness. Our findings reveal significant differences in structural dynamics and binding energetics between the apo and complex forms of PANK3, shedding light on the mechanisms underlying ligand binding and enzymatic function. Additionally, community network analysis elucidates long-range communications and allosteric effects within the protein structure, providing insights into its functional regulation.