scholarly journals Structural Analysis and Design of Chionodracine-Derived Peptides Using Circular Dichroism and Molecular Dynamics Simulations

2020 ◽  
Vol 21 (4) ◽  
pp. 1401
Author(s):  
Stefano Borocci ◽  
Giulia Della Pelle ◽  
Francesca Ceccacci ◽  
Cristina Olivieri ◽  
Francesco Buonocore ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Circular Dichroism ◽  
Lipid Membranes ◽  
Lipid Vesicles ◽  
Md Simulations ◽  
Structural Basis ◽  
Human Pathogens ◽  
Analysis And Design ◽  
Dynamics Simulations ◽  
Circular Dichroïsm

Antimicrobial peptides have been identified as one of the alternatives to the extensive use of common antibiotics as they show a broad spectrum of activity against human pathogens. Among these is Chionodracine (Cnd), a host-defense peptide isolated from the Antarctic icefish Chionodraco hamatus, which belongs to the family of Piscidins. Previously, we demonstrated that Cnd and its analogs display high antimicrobial activity against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species). Herein, we investigate the interactions with lipid membranes of Cnd and two analogs, Cnd-m3 and Cnd-m3a, showing enhanced potency. Using a combination of Circular Dichroism, fluorescence spectroscopy, and all-atom Molecular Dynamics (MD) simulations, we determined the structural basis for the different activity among these peptides. We show that all peptides are predominantly unstructured in water and fold, preferentially as α-helices, in the presence of lipid vesicles of various compositions. Through a series of MD simulations of 400 ns time scale, we show the effect of mutations on the structure and lipid interactions of Cnd and its analogs. By explaining the structural basis for the activity of these analogs, our findings provide structural templates to design minimalistic peptides for therapeutics.

scholarly journals PDBMD2CD: providing predicted protein circular dichroism spectra from multiple molecular dynamics-generated protein structures

2020 ◽  
Vol 48 (W1) ◽  
pp. W17-W24 ◽  
Author(s):  
Elliot D Drew ◽  
Robert W Janes
Keyword(s):  
Molecular Dynamics ◽  
Circular Dichroism ◽  
Protein Structures ◽  
Experimental Spectrum ◽  
Md Simulations ◽  
Resonance Spectroscopy ◽  
Cd Spectra ◽  
Structure Information ◽  
Multiple Protein ◽  
Circular Dichroïsm

Abstract PDBMD2CD is a new web server capable of predicting circular dichroism (CD) spectra for multiple protein structures derived from molecular dynamics (MD) simulations, enabling predictions from thousands of protein atomic coordinate files (e.g. MD trajectories) and generating spectra for each of these structures provided by the user. Using MD enables exploration of systems that cannot be monitored by direct experimentation. Validation of MD-derived data from these types of trajectories can be difficult via conventional structure-determining techniques such as crystallography or nuclear magnetic resonance spectroscopy. CD is an experimental technique that can provide protein structure information from such conditions. The website utilizes a much faster (minimum ∼1000×) and more accurate approach for calculating CD spectra than its predecessor, PDB2CD (1). As well as improving on the speed and accuracy of current methods, new analysis tools are provided to cluster predictions or compare them against experimental CD spectra. By identifying a subset of the closest predicted CD spectra derived from PDBMD2CD to an experimental spectrum, the associated cluster of structures could be representative of those found under the conditions in which the MD studies were undertaken, thereby offering an analytical insight into the results. PDBMD2CD is freely available at: https://pdbmd2cd.cryst.bbk.ac.uk.

Molecular Dynamics Simulations of Adenosine Receptors: Advances, Applications and Trends

2019 ◽  
Vol 25 (7) ◽  
pp. 783-816 ◽  
Author(s):  
Nizar A. Al-Shar'i ◽  
Qosay A. Al-Balas
Keyword(s):  
Molecular Dynamics ◽  
Adenosine Receptors ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Relevant Literature ◽  
Md Simulations ◽  
Structural Basis ◽  
Structural And Functional Properties ◽  
Starting Point ◽  
Dynamics Simulations

: Adenosine receptors (ARs) are transmembrane proteins that belong to the G protein-coupled receptors (GPCRs) superfamily and mediate the biological functions of adenosine. To date, four AR subtypes are known, namely A1, A2A, A2B and A3 that exhibit different signaling pathways, tissue localization, and mechanisms of activation. Moreover, the widespread ARs and their implication in numerous physiological and pathophysiological conditions had made them pivotal therapeutic targets for developing clinically effective agents. : The crystallographic success in identifying the 3D crystal structures of A2A and A1 ARs has dramatically enriched our understanding of their structural and functional properties such as ligand binding and signal transduction. This, in turn, has provided a structural basis for a larger contribution of computational methods, particularly molecular dynamics (MD) simulations, toward further investigation of their molecular properties and designing bioactive ligands with therapeutic potential. MD simulation has been proved to be an invaluable tool in investigating ARs and providing answers to some critical questions. For example, MD has been applied in studying ARs in terms of ligand-receptor interactions, molecular recognition, allosteric modulations, dimerization, and mechanisms of activation, collectively aiding in the design of subtype selective ligands. : In this review, we focused on the advances and different applications of MD simulations utilized to study the structural and functional aspects of ARs that can foster the structure-based design of drug candidates. In addition, relevant literature was briefly discussed which establishes a starting point for future advances in the field of drug discovery to this pivotal group of drug targets.

scholarly journals Electronic Circular Dichroism Spectra of DNA Quadruple Helices Studied by Molecular Dynamics Simulations and Excitonic Calculations Including Charge Transfer States

Molecules ◽  
2021 ◽  
Vol 26 (16) ◽  
pp. 4789
Author(s):  
Haritha Asha ◽  
James A. Green ◽  
Lara Martinez-Fernandez ◽  
Luciana Esposito ◽  
Roberto Improta
Keyword(s):  
Molecular Dynamics ◽  
Circular Dichroism ◽  
Charge Transfer ◽  
Molecular Dynamics Simulations ◽  
Thermal Fluctuations ◽  
Telomeric Sequence ◽  
Quadruple Helix ◽  
Electronic Circular Dichroism ◽  
Dynamics Simulations ◽  
Circular Dichroïsm

We here investigate the Electronic Circular Dichroism (ECD) Spectra of two representative Guanine-rich sequences folded in a Quadruple helix (GQ), by using a recently developed fragment diabatisation based excitonic model (FrDEx). FrDEx can include charge transfer (CT) excited states and consider the effect of the surrounding monomers on the local excitations (LEs). When applied to different structures generated by molecular dynamics simulations on a fragment of the human telomeric sequence (Tel21/22), FrDEx provides spectra fully consistent with the experimental one and in good agreement with that provided by quantum mechanical (QM) method used for its parametrization, i.e., TD-M05-2X. We show that the ECD spectrum is moderately sensitive to the conformation adopted by the bases of the loops and more significantly to the thermal fluctuations of the Guanine tetrads. In particular, we show how changes in the overlap of the tetrads modulate the intensity of the ECD signal. We illustrate how this correlates with changes in the character of the excitonic states at the bottom of the La and Lb bands, with larger LE and CT involvement of bases that are more closely stacked. As an additional test, we utilised FrDEx to compute the ECD spectrum of the monomeric and dimeric forms of a GQ forming sequence T30695 (5’TGGGTGGGTGGGTGGG3’), i.e., a system containing up to 24 Guanine bases, and demonstrated the satisfactory reproduction of the experimental and QM reference results. This study provides new insights on the effects modulating the ECD spectra of GQs and, more generally, further validates FrDEx as an effective tool to predict and assign the spectra of closely stacked multichromophore systems.

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