Investigation of the transport cycle of sodium glucose transport proteins through computational simulation.

Abstract

The human Sodium-Glucose Linked Transporter hSGLT2 is responsible for the reabsorption of sugar in the kidneys, and as such is a key target for the treatment of type 2 diabetes. SGLTs are found in the cell membrane and use the sodium gradient to transport sugar into cells through an alternating-access mechanism. Experimentally derived structures of the bacterial homolog vSGLT in an inward-open conformation (apo and substrate bound) and the related sialic acid transporter in an outward-open conformation, along with more recent structures of partially inward-open hSGLT1 and partially outward-open inhibitor-bound hSGLT2, give some insight to the transport mechanism. However, the exact nature of the conformational transition and the energetic details that govern the transport cycle remain unclear. We have used molecular dynamics simulations to explore the dynamics of SGLT in the presence or absence of substrate, including unbiased simulations in different conformations, and weighted ensemble simulations using WESTPA to explore the conformational transition landscape. These simulations demonstrate how the presence of substrate can alter the energetics of the conformational landscape; for example, how sugar may lock the outer gate closed, preventing substrate leaks. Improving our understanding of SGLT function through this work is a key step to better inform the treatment of diabetes and other SGLT-related diseases.