scholarly journals Molecular dynamics simulations informed by membrane lipidomics reveal the structure–interaction relationship of polymyxins with the lipid A-based outer membrane of Acinetobacter baumannii

2020 ◽  
Vol 75 (12) ◽  
pp. 3534-3543 ◽  
Author(s):  
Xukai Jiang ◽  
Kai Yang ◽  
Bing Yuan ◽  
Meiling Han ◽  
Yan Zhu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Acinetobacter Baumannii ◽  
Outer Membrane ◽  
Electrostatic Interactions ◽  
Lipid A ◽  
Gram Negative ◽  
Structure Interaction ◽  
Dynamics Simulations ◽  
Interaction Relationship

Abstract Background MDR bacteria represent an urgent threat to human health globally. Polymyxins are a last-line therapy against life-threatening Gram-negative ‘superbugs’, including Acinetobacter baumannii. Polymyxins exert antimicrobial activity primarily via permeabilizing the bacterial outer membrane (OM); however, the mechanism of interaction between polymyxins and the OM remains unclear at the atomic level. Methods We constructed a lipid A-based OM model of A. baumannii using quantitative membrane lipidomics data and employed all-atom molecular dynamics simulations with umbrella sampling techniques to elucidate the structure–interaction relationship and thermodynamics governing the penetration of polymyxins [B1 and E1 (i.e. colistin A) representing the two clinically used polymyxins] into the OM. Results Polymyxin B1 and colistin A bound to the A. baumannii OM by the initial electrostatic interactions between the Dab residues of polymyxins and the phosphates of lipid A, competitively displacing the cations from the headgroup region of the OM. Both polymyxin B1 and colistin A formed a unique folded conformation upon approaching the hydrophobic centre of the OM, consistent with previous experimental observations. Polymyxin penetration induced reorientation of the headgroups of the OM lipids near the penetration site and caused local membrane disorganization, thereby significantly increasing membrane permeability and promoting the subsequent penetration of polymyxin molecules into the OM and periplasmic space. Conclusions The thermodynamics governing the penetration of polymyxins through the outer leaflet of the A. baumannii OM were examined and novel structure–interaction relationship information was obtained at the atomic and membrane level. Our findings will facilitate the discovery of novel polymyxins against MDR Gram-negative pathogens.

Molecular dynamics simulations of outer-membrane protease T fromE. colibased on a hybrid coarse-grained/atomistic potential

2006 ◽  
Vol 18 (14) ◽  
pp. S347-S355 ◽  
Author(s):  
Marilisa Neri ◽  
Claudio Anselmi ◽  
Vincenzo Carnevale ◽  
Attilio V Vargiu ◽  
Paolo Carloni
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Outer Membrane ◽  
Coarse Grained ◽  
Dynamics Simulations

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

scholarly journals Progress in Molecular Dynamics Simulations of Gram-Negative Bacterial Cell Envelopes

2017 ◽  
Vol 8 (11) ◽  
pp. 2513-2518 ◽  
Author(s):  
Alister Boags ◽  
Pin-Chia Hsu ◽  
Firdaus Samsudin ◽  
Peter J. Bond ◽  
Syma Khalid
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Bacterial Cell ◽  
Gram Negative ◽  
Dynamics Simulations ◽  
Cell Envelopes

scholarly journals Properties of Lipid a Bilayers Analyzed by Molecular Dynamics Simulations

2011 ◽  
Vol 100 (3) ◽  
pp. 321a
Author(s):  
Danielle Stuhlsatz ◽  
Richard Venable ◽  
Wonpil Im
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Lipid A ◽  
Dynamics Simulations

scholarly journals Effect of Ca2+ on the promiscuous target-protein binding mechanism of calmodulin

2018 ◽  
Author(s):  
Annie M. Westerlund ◽  
Lucie Delemotte
Keyword(s):  
Molecular Dynamics ◽  
Protein Binding ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Solvent Exposure ◽  
Conformational States ◽  
Hydrophobic Residues ◽  
Target Proteins ◽  
Flexible Mechanism ◽  
Dynamics Simulations

AbstractCalmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling path- ways. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question.Here, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca2+ modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity.This work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity.Author summaryCalmodulin is a protein involved in the regulation of a variety of cell signaling pathways. It acts by making usually calcium-insensitive proteins sensitive to changes in the calcium concentration inside the cell. Its two lobes bind calcium and allow the energetically unfavorable exposure of hydrophobic residues to the aqueous environment which can then bind target proteins. The mechanisms behind the simultaneous specificity and variation of target protein binding is yet unknown but will aid understanding of the calcium-signaling and regulation that occur in many of our cellular processes.Here, we used molecular dynamics simulations and data analysis techniques to investigate what effect calcium has on the binding modes of calmodulin. The simulations and analyses allow us to observe and differentiate specific states. One domain of calmodulin is shown to be selective with binding involving short- distance interactions between hydrophobic residues, while the other binds target proteins through a more flexible mechanism involving long-distance electrostatic interactions.

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