# Conformational Landscape of the Di- and Tripeptide Permease A Transport Cycle

## TL;DR

This study explores how the DtpA transporter changes shape to move peptides across bacterial cell membranes using proton gradients.

## Contribution

The study reveals how helical interactions drive conformational changes in DtpA during its transport cycle.

## Key findings

- Intra- and inter-helical interactions cause bending and rotation of helices in DtpA.
- These changes lead to pore opening and closure during the transport cycle.
- The findings enhance understanding of bacterial proton-dependent oligopeptide transporters.

## Abstract

Dipeptide and tripeptide
permease A (DtpA) transporter
is a bacterial
homologue of the human PepT that is responsible for the uptake of
di- and tripeptides from the small intestine and transports them across
the cell membrane utilizing an inward-directed proton electrochemical
gradient. Despite its importance, the structural dynamics governing
the conformational transitions of DtpA remain poorly understood. In
this study, we employed Adaptive Bandit enhanced sampling molecular
dynamics simulations to investigate the five major conformational
states of DtpA adopted during the transport cycle. We identified key
metastable states and transitions underlying the transport cycle using
Markov State Models (MSMs). Our findings reveal that intra- and interhelical
interactions drive conformational changes by inducing bending and
rotation of helices lining the pore, resulting in its opening and
closure. This study explains the substrate transport mechanism in
DtpA, enhancing our understanding of bacterial proton-dependent oligopeptide
transporters (POTs) and opening new drug design and development opportunities.