Molecular dynamics simulations of temperature-dependent PET binding in PETase, ThermoPETase, and FAST-PETase
Abstract
Polyethylene terephthalate (PET) biodegradation has gained significant attention following the 2016 discovery of the PET-hydrolyzing enzyme IsPETase from Ideonella sakaiensis 201-F6. Although IsPETase operates under mild temperature conditions, its limited catalytic activity and poor thermal stability restrict large-scale industrial applications. To overcome these limitations, several engineered variants have been developed. In this study, the wild-type IsPETase was systematically compared with two engineered variants, ThermoPETase and FAST-PETase, under four temperature conditions (300, 313, 323, and 333 K) using fully detailed atomistic molecular dynamics (MD) simulations. A PET dimer was docked into the active site of each enzyme, followed by 150 ns of restrained and unrestrained MD simulations to evaluate structural stability and substrate interactions. Both engineered variants exhibited improved thermal stability relative to IsPETase, with FAST-PETase demonstrating the highest stability across all temperatures. Increased flexibility of the catalytic triad was observed in both engineered variants, suggesting enhanced catalytic adaptability compared to IsPETase. Key residues, Tyr87 and Met161, were identified as essential for stabilizing the PET dimer within the active-site cavity. At elevated temperature (333 K), IsPETase showed increased flexibility, leading to disrupted PET dimer binding. In contrast, ThermoPETase and FAST-PETase preserved stable PET dimer positioning…
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