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Molecular Dynamics of Membrane Proteins

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (15 May 2024) | Viewed by 2713

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Guest Editor
Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland
Interests: molecular dynamics; molecular modeling; membrane proteins; drug design; G protein-coupled receptors; oligomerization; ligand-protein and protein-protein interactions; macromolecular crowding
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Special Issue Information

Dear Colleagues,

Molecular dynamics simulation is a widely used method for investigating the structural and dynamical properties of proteins. Modern force fields are becoming increasingly accurate in modeling complex biological systems, and the scale of the simulations is growing in both time and space. The use of molecular dynamics to analyze membrane proteins resulted in a better understanding of their stability and function in their specific environment. This Special Issue intends to publish reviews and original research articles involving all aspects of the application and development of molecular dynamics methodology for membrane proteins. Research on single proteins as well as their assemblies is welcome. Not only computer simulations, but also experimental studies that provide a dynamic picture of membrane proteins fit well within the scope of this Special Issue. I welcome contributions presenting important and up-to-date studies on the molecular dynamics of membrane proteins.

Prof. Dr. Sławomir Filipek
Guest Editor

Manuscript Submission Information

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Keywords

  • molecular dynamics
  • force fields
  • membrane proteins
  • macromolecular crowding
  • oligomerization
  • coarse-graining
  • enhanced sampling
  • lipid–protein interactions

Published Papers (3 papers)

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17 pages, 3755 KiB  
Article
Molecular Dynamics Simulations of the Mutated Proton-Transferring a-Subunit of E. coli FoF1-ATP Synthase
by Leonid A. Ivontsin, Elena V. Mashkovtseva and Yaroslav R. Nartsissov
Int. J. Mol. Sci. 2024, 25(10), 5143; https://doi.org/10.3390/ijms25105143 - 9 May 2024
Viewed by 273
Abstract
The membrane Fo factor of ATP synthase is highly sensitive to mutations in the proton half-channel leading to the functional blocking of the entire protein. To identify functionally important amino acids for the proton transport, we performed molecular dynamic simulations on the [...] Read more.
The membrane Fo factor of ATP synthase is highly sensitive to mutations in the proton half-channel leading to the functional blocking of the entire protein. To identify functionally important amino acids for the proton transport, we performed molecular dynamic simulations on the selected mutants of the membrane part of the bacterial FoF1-ATP synthase embedded in a native lipid bilayer: there were nine different mutations of a-subunit residues (aE219, aH245, aN214, aQ252) in the inlet half-channel. The structure proved to be stable to these mutations, although some of them (aH245Y and aQ252L) resulted in minor conformational changes. aH245 and aN214 were crucial for proton transport as they directly facilitated H+ transfer. The substitutions with nonpolar amino acids disrupted the transfer chain and water molecules or neighboring polar side chains could not replace them effectively. aE219 and aQ252 appeared not to be determinative for proton translocation, since an alternative pathway involving a chain of water molecules could compensate the ability of H+ transmembrane movement when they were substituted. Thus, mutations of conserved polar residues significantly affected hydration levels, leading to drastic changes in the occupancy and capacity of the structural water molecule clusters (W1–W3), up to their complete disappearance and consequently to the proton transfer chain disruption. Full article
(This article belongs to the Special Issue Molecular Dynamics of Membrane Proteins)
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17 pages, 4197 KiB  
Article
Conformational Changes and Unfolding of β-Amyloid Substrates in the Active Site of γ-Secretase
by Jakub Jakowiecki, Urszula Orzeł, Przemysław Miszta, Krzysztof Młynarczyk and Sławomir Filipek
Int. J. Mol. Sci. 2024, 25(5), 2564; https://doi.org/10.3390/ijms25052564 - 22 Feb 2024
Viewed by 660
Abstract
Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes [...] Read more.
Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ40 and Aβ42, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ40, indicating why trimming of this substrate is so infrequent. Full article
(This article belongs to the Special Issue Molecular Dynamics of Membrane Proteins)
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17 pages, 2579 KiB  
Article
Toward Overcoming Pyrethroid Resistance in Mosquito Control: The Role of Sodium Channel Blocker Insecticides
by Beata Niklas, Jakub Rydzewski, Bruno Lapied and Wieslaw Nowak
Int. J. Mol. Sci. 2023, 24(12), 10334; https://doi.org/10.3390/ijms241210334 - 19 Jun 2023
Viewed by 1177
Abstract
Diseases spread by mosquitoes lead to the death of 700,000 people each year. The main way to reduce transmission is vector control by biting prevention with chemicals. However, the most commonly used insecticides lose efficacy due to the growing resistance. Voltage-gated sodium channels [...] Read more.
Diseases spread by mosquitoes lead to the death of 700,000 people each year. The main way to reduce transmission is vector control by biting prevention with chemicals. However, the most commonly used insecticides lose efficacy due to the growing resistance. Voltage-gated sodium channels (VGSCs), membrane proteins responsible for the depolarizing phase of an action potential, are targeted by a broad range of neurotoxins, including pyrethroids and sodium channel blocker insecticides (SCBIs). Reduced sensitivity of the target protein due to the point mutations threatened malaria control with pyrethroids. Although SCBIs—indoxacarb (a pre-insecticide bioactivated to DCJW in insects) and metaflumizone—are used in agriculture only, they emerge as promising candidates in mosquito control. Therefore, a thorough understanding of molecular mechanisms of SCBIs action is urgently needed to break the resistance and stop disease transmission. In this study, by performing an extensive combination of equilibrium and enhanced sampling molecular dynamics simulations (3.2 μs in total), we found the DIII-DIV fenestration to be the most probable entry route of DCJW to the central cavity of mosquito VGSC. Our study revealed that F1852 is crucial in limiting SCBI access to their binding site. Our results explain the role of the F1852T mutation found in resistant insects and the increased toxicity of DCJW compared to its bulkier parent compound, indoxacarb. We also delineated residues that contribute to both SCBIs and non-ester pyrethroid etofenprox binding and thus could be involved in the target site cross-resistance. Full article
(This article belongs to the Special Issue Molecular Dynamics of Membrane Proteins)
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