Affinity and path of binding xylopyranose unto E. coli xylose permease

Abstract

Glucose transporters (GLUTs), expressed in all types of human cells, are responsible for the uptake of sugars as the primary energy source for the normal functions of good cells and for the abnormal growth of cancer cells. The E. coli xylose permease (XylE), a homologue of human GLUTs, has been investigated more thoroughly than other major facilitator proteins in the current literature. In this paper, we present a molecular dynamics (MD) study of an all-atom model system to elucidate the atomistic details and the free-energy landscape along the path of binding a xylopyranose (XYP) from the extracellular space to the inside of the transporter protein XylE. From the MD simulations, the Gibbs free energy of binding was found to be −4.4 kcal/mol in agreement with the experimental value of −4.7 kcal/mol. The accuracy of our study is further shown in the computed hydration energy of XYP of −14.6 kcal/mol in comparison with the experimental data of −15.0 kcal/mol. Along the binding path, the Gibbs free energy of the XYP-XylE complex first rises from zero in the dissociated state to approximately 4 kcal/mol in the transition state (when XylE slightly increases its opening toward the extracellular side to accommodate XYP) before dropping down to −9.0 kcal/mol in the bound state. These quantitative insights indicate the fast equilibration between the bound and the unbound states of XylE and XYP. They also serve as an atomistic-dynamic corroboration of the experimental conclusion that XylE is a high-affinity sugar transporter.

Thermodynamics and Kinetics of Drug-Target Binding by Molecular Simulation

“…Recent works have used this technique to study the following targets: focal adhesion kinase, 220 the cancer target LSD1, 221 neuraminidase, 222 FK506 binding protein together with trypsin and cyclin-dependent kinase 2, 223 xylose permease, 224 and enzyme 5-enolpyruvylshikimate 3 phosphate synthase. 225 Summarizing this section, absolute binding energy computations are now computationally feasible, up to the accuracy limit of existing force fields, and of finite sampling of the relevant phase space.…”

“…Recent works have used this technique to study the following targets: focal adhesion kinase, the cancer target LSD1, neuraminidase, FK506 binding protein together with trypsin and cyclin-dependent kinase 2, xylose permease, and enzyme 5-enolpyruvylshikimate 3 phosphate synthase …”

Extracellular gating of glucose transport through GLUT 1

“…Interestingly, in two recent studies, the structure and activities of GLUTs were shown to depend on the membrane lipid composition [54] and lipid (fluid/gel) phase [55]. In contrast, most MD simulations on GLUTs of the current literature [51][52][53][55][56][57] have the cell membrane modelled as a symmetric bilayer of a single lipid type.…”

Quantitative characterization of the path of glucose diffusion facilitated by human glucose transporter 1

“…Most molecular dynamics (MD) simulations, e.g., (44)(45)(46)(47), were focused on conforming with the alternating access theory (1,48) that is thought to be universally applicable for all MFS transporters including GLUT1. All these and most other MD simulations on GLUTs (44)(45)(46)(47)(49)(50)(51) have the cell membrane modelled as a symmetric bilayer of a single lipid type. They do not heed the known facts that the structure and activities of GLUTs are sensitive to the membrane lipid compositions.…”

“…In light of all these, surveying the current literature of molecular dynamics (MD) simulations of GLUT1, e.g., [46,[54][55][56][57][58], and some other GLUTs [55][56][57][58][59][60][61], one can see the need to further the current MD studies by modelling a cell membrane with two asymmetries between the intracellular (IC) and the extracellular (EC) sides of the membrane: (1) asymmetric lipid compositions of the inner and the outer leaflets and (2) asymmetric saline compositions of the aqueous compartments on the IC and the EC sides of the membrane. A recent MD study [46] included the asymmetry of the first type mimicking the lipid compositions of human erythrocyte.…”