scholarly journals Elevator-type mechanisms of membrane transport

2020 ◽  
Vol 48 (3) ◽  
pp. 1227-1241 ◽  
Author(s):  
Alisa A. Garaeva ◽  
Dirk J. Slotboom
Keyword(s):  
Lipid Bilayers ◽  
Conformational Changes ◽  
Conformational Transitions ◽  
Membrane Transporters ◽  
Integral Membrane Proteins ◽  
Protein Domain ◽  
Aqueous Environment ◽  
Dynamics Simulations ◽  
Structural Solutions ◽  
Alternating Access

Membrane transporters are integral membrane proteins that mediate the passage of solutes across lipid bilayers. These proteins undergo conformational transitions between outward- and inward-facing states, which lead to alternating access of the substrate-binding site to the aqueous environment on either side of the membrane. Dozens of different transporter families have evolved, providing a wide variety of structural solutions to achieve alternating access. A sub-set of structurally diverse transporters operate by mechanisms that are collectively named ‘elevator-type’. These transporters have one common characteristic: they contain a distinct protein domain that slides across the membrane as a rigid body, and in doing so it ‘drags” the transported substrate along. Analysis of the global conformational changes that take place in membrane transporters using elevator-type mechanisms reveals that elevator-type movements can be achieved in more than one way. Molecular dynamics simulations and experimental data help to understand how lipid bilayer properties may affect elevator movements and vice versa.

scholarly journals Exploring Conformational Transitions and Free Energy Profiles of Proton Coupled Oligopeptide Transporters

2019 ◽  
Author(s):  
Mariana R. B. Batista ◽  
Anthony Watts ◽  
Antonio J. Costa-Filho
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Conformational Transitions ◽  
Peptide Transport ◽  
Conformational Variability ◽  
Energy Profiles ◽  
Comprehensive Picture ◽  
Adaptive Biasing ◽  
Dynamics Simulations ◽  
Free Energy Profiles

AbstractProteins involved in peptide uptake and transport belong to the proton-coupled oligopeptide transporter (POT) family. Crystal structures of POT family members reveal a common fold consisting of two domains of six transmembrane α helices that come together to form a “V” shaped transporter with a central substrate binding site. Proton coupled oligopeptide transporters operate through an alternate access mechanism, where the membrane transporter undergoes global conformational changes, alternating between inward-facing (IF), outward-facing (OF) and occluded (OC) states. Conformational transitions are promoted by proton and ligand binding, however, due to the absence of crystallographic models of the outward-open state, the role of H+ and ligands are still not fully understood. To provide a comprehensive picture of the POT conformational equilibrium, conventional and enhanced sampling molecular dynamics simulations of PepTst in the presence or absence of ligand and protonation were performed. Free energy profiles of the conformational variability of PepTst were obtained from microseconds of adaptive biasing force (ABF) simulations. Our results reveal that both, proton and ligand, significantly change the conformational free energy landscape. In the absence of ligand and protonation, only transitions involving IF and OC states are allowed. After protonation of the residue Glu300, the wider free energy well for Glu300 protonated PepTst indicates a greater conformational variability relative to the apo system, and OF conformations becames accessible. For the Glu300 Holo-PepTst, the presence of a second free energy minimum suggests that OF conformations are not only accessible, but also, stable. The differences in the free energy profiles demonstrate that transitions toward outward facing conformation occur only after protonation and, probably, this should be the first step in the mechanism of peptide transport. Our extensive ABF simulations provide a fully atomic description of all states of the transport process, offering a model for the alternating access mechanism and how protonation and ligand control the conformational changes.Graphical TOC Entry

scholarly journals Atomic-level characterization of conformational transition and substrate binding of xCT transporter

2018 ◽  
Author(s):  
M. Sharma ◽  
A. C. Rohithaswa
Keyword(s):  
Ligand Binding ◽  
Conformational Changes ◽  
Bound States ◽  
Conformational Transition ◽  
Substrate Binding ◽  
Transmembrane Helices ◽  
Neurological Processes ◽  
Dynamics Simulations ◽  
Alternating Access

AbstractxCT is a component of heterodimeric amino acids transporter system Xc- that has been known to work at the cross-roads of maintaining neurological processes and regulating antioxidant defense. xCT is a sodium-independent amino acid antiporter, that imports L- cystine and exports L-glutamate in a 1:1 ratio. The transporter has 12 transmembrane domains with intracellular N- and C-termini, which can undergo various conformational changes while switching the ligand accessibilities from intracellular to extracellular site. In the present study, we generated two homology models of human xCT in two distinct conformations: inward facing occluded state and outward facing open state. We investigated the conformational transitions within these two states by employing series of targeted molecular dynamics simulations. Our results indicated the substrate translocation channel composed of transmembrane helices TMs 1, 3, 6, 8, and 10. Further, we analyzed the ligand binding within the intermediate conformations obtained from the transition simulations. We docked anionic L-cystine and L-glutamate within the cavities alone or in combination to assess the two distinct binding scenarios for xCT as antiporter. We also assessed the interactions between the ligand and xCT and observed that ligands bind to similar residues within the channel, and these residues are essential for substrate binding/permeation. In addition, we analyzed the correlations between ligand binding and conformational transition and observed conformations that are representatives for intermediate ligand bound states. The results presented in the study provide insights into the interplay of conformational transition and ligand binding as xCT goes from one probable conformation to another while transporting the ligand. And the data thus adds to the existing evidence of alternating access mechanism pertaining to the functioning of transporters.

On the Adsorption of Aspartate Derivatives to Calcite Surfaces in Aqueous Environment

2020 ◽  
Author(s):  
Robert Stepic ◽  
Lara Jurković ◽  
Ksenia Klementyeva ◽  
Marko Ukrainczyk ◽  
Matija Gredičak ◽  
...  
Keyword(s):  
Active Sites ◽  
Realistic Model ◽  
Binding Energies ◽  
Inhibition Mechanism ◽  
Aqueous Environment ◽  
Binding Modes ◽  
Carboxylate Groups ◽  
Dissolved Ions ◽  
Living Organisms ◽  
Dynamics Simulations

In many living organisms, biomolecules interact favorably with various surfaces of calcium carbonate. In this work, we have considered the interactions of aspartate (Asp) derivatives, as models of complex biomolecules, with calcite. Using kinetic growth experiments, we have investigated the inhibition of calcite growth by Asp, Asp2 and Asp3.This entailed the determination of a step-pinning growth regime as well as the evaluation of the adsorption constants and binding free energies for the three species to calcite crystals. These latter values are compared to free energy profiles obtained from fully atomistic molecular dynamics simulations. When using a flat (104) calcite surface in the models, the measured trend of binding energies is poorly reproduced. However, a more realistic model comprised of a surface with an island containing edges and corners, yields binding energies that compare very well with experiments. Surprisingly, we find that most binding modes involve the positively charged, ammonium group. Moreover, while attachment of the negatively charged carboxylate groups is also frequently observed, it is always balanced by the aqueous solvation of an equal or greater number of carboxylates. These effects are observed on all calcite features including edges and corners, the latter being associated with dominant affinities to Asp derivatives. As these features are also precisely the active sites for crystal growth, the experimental and theoretical results point strongly to a growth inhibition mechanism whereby these sites become blocked, preventing further attachment of dissolved ions and halting further growth.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Lipid Transporters Beam Signals from Cell Membranes

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 562
Author(s):  
Miliça Ristovski ◽  
Danny Farhat ◽  
Shelly Ellaine M. Bancud ◽  
Jyh-Yeuan Lee
Keyword(s):  
Membrane Proteins ◽  
Lipid Bilayers ◽  
Lipid Composition ◽  
Structural Integrity ◽  
Current Knowledge ◽  
Integral Membrane Proteins ◽  
Cellular Membranes ◽  
Cytoplasmic Proteins ◽  
Lipid Transporters

Lipid composition in cellular membranes plays an important role in maintaining the structural integrity of cells and in regulating cellular signaling that controls functions of both membrane-anchored and cytoplasmic proteins. ATP-dependent ABC and P4-ATPase lipid transporters, two integral membrane proteins, are known to contribute to lipid translocation across the lipid bilayers on the cellular membranes. In this review, we will highlight current knowledge about the role of cholesterol and phospholipids of cellular membranes in regulating cell signaling and how lipid transporters participate this process.

scholarly journals Studies of Conformational Changes of Tubulin Induced by Interaction with Kinesin Using Atomistic Molecular Dynamics Simulations

2021 ◽  
Vol 22 (13) ◽  
pp. 6709
Author(s):  
Xiao-Xuan Shi ◽  
Peng-Ye Wang ◽  
Hong Chen ◽  
Ping Xie
Keyword(s):  
Molecular Dynamics ◽  
High Resolution ◽  
Binding Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Weak Interactions ◽  
Molecular Motor ◽  
Structural Data ◽  
Calculated Binding Energy ◽  
Dynamics Simulations

The transition between strong and weak interactions of the kinesin head with the microtubule, which is regulated by the change of the nucleotide state of the head, is indispensable for the processive motion of the kinesin molecular motor on the microtubule. Here, using all-atom molecular dynamics simulations, the interactions between the kinesin head and tubulin are studied on the basis of the available high-resolution structural data. We found that the strong interaction can induce rapid large conformational changes of the tubulin, whereas the weak interaction cannot. Furthermore, we found that the large conformational changes of the tubulin have a significant effect on the interaction of the tubulin with the head in the weak-microtubule-binding ADP state. The calculated binding energy of the ADP-bound head to the tubulin with the large conformational changes is only about half that of the tubulin without the conformational changes.

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