Kinetic Network Modeling with Molecular Simulation Inputs: A Proton-Coupled Phosphate Symporter

Biophys J. 2024 Mar 27:S0006-3495(24)00216-9. doi: 10.1016/j.bpj.2024.03.035. Online ahead of print.ABSTRACTPhosphate, an essential metabolite involved in numerous cellular functions, is taken up by proton-coupled phosphate transporters of plants and fungi within the major facilitator family. Similar phosphate transporters have been identified across a diverse range of biological entities, including various protozoan parasites linked to human diseases, breast cancer cells with increased phosphate requirements, and osteoclast-like cells engaged in bone resorption. Prior studies have proposed an overview of the functional cycle of a proton-driven phosphate transporter (PiPT), yet a comprehensive understanding of the proposed reaction pathways necessitates a closer examination of each elementary reaction step within an overall kinetic framework. In this work, we leverage kinetic network modeling in conjunction with a "bottom-up" molecular dynamics approach to show how such an approach can characterize the proton-phosphate co-transport behavior of PiPT under different pH and phosphate concentration conditions. In turn, this allows us to reveal the prevailing reaction pathway within a high-affinity phosphate transporter under different experimental conditions and to uncover the molecular origin of the optimal pH condition of this transporter.PMID:38549372 | DOI:10.1016/j.bpj.2024.03.035
Source: Biophysical Journal - Category: Physics Authors: Source Type: research