Modeling of flux, binding and substitution of urea molecules in the urea transporter dvUT

Abstract

Urea transporters (UTs) are transmembrane proteins that transport urea molecules across cell membranes and play a crucial role in urea excretion and water balance. Modeling the functional characteristics of UTs helps us understand how their structures accomplish the functions at the atomic level, and facilitates future therapeutic design targeting the UTs. This study was based on the crystal structure of Desulfovibrio vulgaris urea transporter (dvUT). To model the binding behavior of urea molecules in dvUT, we constructed a cooperative binding model. To model the substitution of urea by the urea analogue N,N′-dimethylurea (DMU) in dvUT, we calculated the occupation probability of DMU along the urea pore and the ratio of the occupation probabilities of DMU at the external (Sext) and internal (Sint) binding sites, and we established the mutual substitution rule for binding and substitution of urea and DMU. Based on these calculations and modelings, together with the use of the Monte Carlo (MC) method, we further modeled the urea flux in dvUT, equilibrium urea binding to dvUT, and the substitution of urea by DMU in the dvUT. Our modeling results are in good agreement with the existing experimental functional data. Furthermore, the modelings have discovered the microscopic process and mechanisms of those functional characteristics. The methods and the results would help our future understanding of the underlying mechanisms of the diseases associated with impaired UT functions and rational drug design for the treatment of these diseases.

Urea-aromatic interactions in biology

“…Wang et al studied both urea and water transport through the dvUT using MD simulations, Monte Carlo methods, and the adaptive biasing force approach (Wang et al 2015b). A computational study modeled the urea flux in dvUT, the equilibrium urea binding to dvUT, as well as the substitution of urea by DMU in the dvUT (Zhang et al 2017). Another investigation by Padhi and co-workers elucidated the urea permeation mechanism employing umbrella sampling MD simulations (Padhi and Priyakumar 2016).…”