Mechanistic Picture for Chemomechanical Coupling in a Bacterial Proton-Coupled Oligopeptide Transporter from Streptococcus Thermophilus

Abstract

Proton-coupled oligopeptide transporters (POTs) use the proton electrochemical gradient to transport peptides across the cell membrane. Despite the significant biological and biomedical relevance of these proteins, a detailed mechanistic picture for chemomechanical couplings involved in substrate/ proton transport and protein structural changes is missing. Therefore, we performed microsecond-level molecular dynamics simulations of bacterial POT PepT St , which shares ∼80% sequence identity with the human POT, PepT1, in the substrate-binding region. Three different conformational states of PepT St were simulated, including (i) occluded, apo, (ii) inward-facing, apo, and (iii) inward-facing occluded , Leu−Ala bound. We propose that the interaction of R33 with E299 and E300 acts as a conformational switch (i.e., to trigger the conformational change from an inward-to outward-facing state) in the substrate transport. Additionally, we propose that E299 and E400 disengage from interacting with the substrate either through protonation or through coordination with a cation for the substrate to get transported. This study provides clues to understand the chemomechanical couplings in POTs and paves the way to decipher the molecular-level underpinnings of the structure−function relationship in this important family of transporters.

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

“…There are a number of studies and reviews on how cholesterol modulates class A GPCRs, but this area of study is yet to be fully explored for class C GPCRs. Recent advances in experimental and computational power have enabled researchers to investigate the role of lipids in various membranes and solvable proteins, at the atomic level using molecular dynamics simulation [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].…”

Cholesterol in Class C GPCRs: Role, Relevance, and Localization

“…There are a number of studies and reviews on how cholesterol modulates class A GPCRs, but this area of study is yet to be fully explored for class C GPCRs. Recent advances in experimental and computational power have enabled researchers to investigate the role of lipids in various membranes and solvable proteins, at the atomic level using molecular dynamics simulation [8][9][10][11][12][13].…”

Elucidating the molecular basis of spontaneous activation in an engineered mechanosensitive channel

“…MD is a powerful computational tool that is used, among other things, to study various therapeutically important targets at an atomic level [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] . Several MD studies using coarse-grained MD [41] , [42] , [43] or biased MD [44] , [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] , [53] , [54] , [55] , [56] , [57] , have been conducted thus far for studying the activation of wild-type (WT) MscL.…”