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Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics
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Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics

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

Deadline for manuscript submissions: closed (15 January 2024) | Viewed by 7120

Special Issue Editors

Prof. Dr. Yuriy F. Zuev

E-Mail Website
Guest Editor
Kazan Institute of Biochemistry and Biophysics of FRC Kazan Scientific Center of Rassian Academy of Sciences, 420111 Kazan, Russia
Interests: biophysics and physical chemistry of biomacromolecules, structure and functions
Special Issues, Collections and Topics in MDPI journals
Dr. Igor Sedov

E-Mail Website
Guest Editor
Chemical Institute, Kazan Federal University, 420008 Kazan, Russia
Interests: biophysical chemistry; computer simulations; solution thermodynamics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein–ligand interactions have remained a broad and important field of study over many years. In living organisms, chemically diverse ligands interacting with proteins can play many different roles, such as enzyme substrates, allosteric effectors, signal transmitters, etc. Inorganic ions, small organic molecules, biopolymers, and synthetic polymers are all able to interact with proteins. Rapidly improving biophysical and computational techniques have allowed for the obtainment of quantitative characteristics of protein–ligand interactions, including ligand affinity, kinetics of binding, and the structure of complexes. These data are necessary for fundamental biology, drug discovery, the development of personalized medicine, biotechnology, and food processing.

The present Special Issue entitled “Protein–Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics” aims to cover the multidisciplinary research results at the intersection of physics, biology, chemistry, computer science, medicine, and/or materials science.

This Special Issue is supervised by Prof. Dr. Yuriy F. Zuev, Prof. Dr. Igor Sedov, and assisted by Dr. Alexandra Kusova.

Prof. Dr. Yuriy F. Zuev
Dr. Igor Sedov
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein–ligand interactions
  • enzyme–substrate recognition
  • signaling molecules and receptors
  • polysaccharide–protein complexation
  • allosteric effectors
  • biophysical techniques
  • structural bioinformatics
  • rational drug design
  • target discovery

Published Papers (5 papers)

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Research

16 pages, 22375 KiB  
Article
Identifying Residues for Substrate Recognition in Human GPAT4 by Molecular Dynamics Simulations
by Yulan Liu, Yunong Xu, Yinuo Xu, Zhihao Zhao, Gui-Juan Cheng, Ruobing Ren and Ying-Chih Chiang
Int. J. Mol. Sci. 2024, 25(7), 3729; https://doi.org/10.3390/ijms25073729 - 27 Mar 2024
Viewed by 513
Abstract
Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step in triacylglycerol synthesis. Understanding its substrate recognition mechanism may help to design drugs to regulate the production of glycerol lipids in cells. In this work, we investigate how the native substrate, glycerol-3-phosphate (G3P), and palmitoyl-coenzyme A [...] Read more.
Glycerol-3-phosphate acyltransferase (GPAT) catalyzes the first step in triacylglycerol synthesis. Understanding its substrate recognition mechanism may help to design drugs to regulate the production of glycerol lipids in cells. In this work, we investigate how the native substrate, glycerol-3-phosphate (G3P), and palmitoyl-coenzyme A (CoA) bind to the human GPAT isoform GPAT4 via molecular dynamics simulations (MD). As no experimentally resolved GPAT4 structure is available, the AlphaFold model is employed to construct the GPAT4–substrate complex model. Using another isoform, GPAT1, we demonstrate that once the ligand binding is properly addressed, the AlphaFold complex model can deliver similar results to the experimentally resolved structure in MD simulations. Following the validated protocol of complex construction, we perform MD simulations using the GPAT4–substrate complex. Our simulations reveal that R427 is an important residue in recognizing G3P via a stable salt bridge, but its motion can bring the ligand to different binding hotspots on GPAT4. Such high flexibility can be attributed to the flexible region that exists only on GPAT4 and not on GPAT1. Our study reveals the substrate recognition mechanism of GPAT4 and hence paves the way towards designing GPAT4 inhibitors. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics)
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16 pages, 4309 KiB  
Article
Effects of Homogeneous and Heterogeneous Crowding on Translational Diffusion of Rigid Bovine Serum Albumin and Disordered Alfa-Casein
by Aleksandra M. Kusova, Ilnaz T. Rakipov and Yuriy F. Zuev
Int. J. Mol. Sci. 2023, 24(13), 11148; https://doi.org/10.3390/ijms241311148 - 06 Jul 2023
Cited by 1 | Viewed by 1002
Abstract
Intracellular environment includes proteins, sugars, and nucleic acids interacting in restricted media. In the cytoplasm, the excluded volume effect takes up to 40% of the volume available for occupation by macromolecules. In this work, we tested several approaches modeling crowded solutions for protein [...] Read more.
Intracellular environment includes proteins, sugars, and nucleic acids interacting in restricted media. In the cytoplasm, the excluded volume effect takes up to 40% of the volume available for occupation by macromolecules. In this work, we tested several approaches modeling crowded solutions for protein diffusion. We experimentally showed how the protein diffusion deviates from conventional Brownian motion in artificial conditions modeling the alteration of medium viscosity and rigid spatial obstacles. The studied tracer proteins were globular bovine serum albumin and intrinsically disordered α-casein. Using the pulsed field gradient NMR, we investigated the translational diffusion of protein probes of different structures in homogeneous (glycerol) and heterogeneous (PEG 300/PEG 6000/PEG 40,000) solutions as a function of crowder concentration. Our results showed fundamentally different effects of homogeneous and heterogeneous crowded environments on protein self-diffusion. In addition, the applied “tracer on lattice” model showed that smaller crowding obstacles (PEG 300 and PEG 6000) create a dense net of restrictions noticeably hindering diffusing protein probes, whereas the large-sized PEG 40,000 creates a “less restricted” environment for the diffusive motion of protein molecules. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics)
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22 pages, 9370 KiB  
Article
Molecular Docking of Lac_CB10: Highlighting the Great Potential for Bioremediation of Recalcitrant Chemical Compounds by One Predicted Bacteroidetes CopA-Laccase
by Bárbara Bonfá Buzzo, Silvana Giuliatti, Pâmela Aparecida Maldaner Pereira, Elisângela Soares Gomes-Pepe and Eliana Gertrudes de Macedo Lemos
Int. J. Mol. Sci. 2023, 24(12), 9785; https://doi.org/10.3390/ijms24129785 - 06 Jun 2023
Cited by 1 | Viewed by 1394
Abstract
Laccases are multicopper oxidases (MCOs) with a broad application spectrum, particularly in second-generation ethanol biotechnology and the bioremediation of xenobiotics and other highly recalcitrant compounds. Synthetic pesticides are xenobiotics with long environmental persistence, and the search for their effective bioremediation has mobilized the [...] Read more.
Laccases are multicopper oxidases (MCOs) with a broad application spectrum, particularly in second-generation ethanol biotechnology and the bioremediation of xenobiotics and other highly recalcitrant compounds. Synthetic pesticides are xenobiotics with long environmental persistence, and the search for their effective bioremediation has mobilized the scientific community. Antibiotics, in turn, can pose severe risks for the emergence of multidrug-resistant microorganisms, as their frequent use for medical and veterinary purposes can generate constant selective pressure on the microbiota of urban and agricultural effluents. In the search for more efficient industrial processes, some bacterial laccases stand out for their tolerance to extreme physicochemical conditions and their fast generation cycles. Accordingly, to expand the range of effective approaches for the bioremediation of environmentally important compounds, the prospection of bacterial laccases was carried out from a custom genomic database. The best hit found in the genome of Chitinophaga sp. CB10, a Bacteroidetes isolate obtained from a biomass-degrading bacterial consortium, was subjected to in silico prediction, molecular docking, and molecular dynamics simulation analyses. The putative laccase CB10_180.4889 (Lac_CB10), composed of 728 amino acids, with theoretical molecular mass values of approximately 84 kDa and a pI of 6.51, was predicted to be a new CopA with three cupredoxin domains and four conserved motifs linking MCOs to copper sites that assist in catalytic reactions. Molecular docking studies revealed that Lac_CB10 had a high affinity for the molecules evaluated, and the affinity profiles with multiple catalytic pockets predicted the following order of decreasing thermodynamically favorable values: tetracycline (−8 kcal/mol) > ABTS (−6.9 kcal/mol) > sulfisoxazole (−6.7 kcal/mol) > benzidine (−6.4 kcal/mol) > trimethoprim (−6.1 kcal/mol) > 2,4-dichlorophenol (−5.9 kcal/mol) mol. Finally, the molecular dynamics analysis suggests that Lac_CB10 is more likely to be effective against sulfisoxazole-like compounds, as the sulfisoxazole-Lac_CB10 complex exhibited RMSD values lower than 0.2 nm, and sulfisoxazole remained bound to the binding site for the entire 100 ns evaluation period. These findings corroborate that LacCB10 has a high potential for the bioremediation of this molecule. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics)
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21 pages, 2596 KiB  
Article
Rapid One-Step Capturing of Native, Cell-Free Synthesized and Membrane-Embedded GLP-1R
by Lisa Haueis, Marlitt Stech, Eberhard Schneider, Thorsten Lanz, Nicole Hebel, Anne Zemella and Stefan Kubick
Int. J. Mol. Sci. 2023, 24(3), 2808; https://doi.org/10.3390/ijms24032808 - 01 Feb 2023
Cited by 4 | Viewed by 2021
Abstract
G protein-coupled receptors (GPCRs) are of outstanding pharmacological interest as they are abundant in cell membranes where they perform diverse functions that are closely related to the vitality of cells. The analysis of GPCRs in natural membranes is laborious, as established methods are [...] Read more.
G protein-coupled receptors (GPCRs) are of outstanding pharmacological interest as they are abundant in cell membranes where they perform diverse functions that are closely related to the vitality of cells. The analysis of GPCRs in natural membranes is laborious, as established methods are almost exclusively cell culture-based and only a few methods for immobilization in a natural membrane outside the cell are known. Within this study, we present a one-step, fast and robust immobilization strategy of the GPCR glucagon-like peptide 1 receptor (GLP-1R). GLP-1R was synthesized in eukaryotic lysates harboring endogenous endoplasmic reticulum-derived microsomes enabling the embedment of GLP-1R in a natural membrane. Interestingly, we found that these microsomes spontaneously adsorbed to magnetic Neutravidin beads thus providing immobilized membrane protein preparations which required no additional manipulation of the target receptor or its supporting membrane. The accessibility of the extracellular domain of membrane-embedded and bead-immobilized GLP-1R was demonstrated by bead-based enzyme-linked immunosorbent assay (ELISA) using GLP-1R-specific monoclonal antibodies. In addition, ligand binding of immobilized GLP-1R was verified in a radioligand binding assay. In summary, we present an easy and straightforward synthesis and immobilization methodology of an active GPCR which can be beneficial for studying membrane proteins in general. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics)
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21 pages, 2650 KiB  
Article
Relations between Structure and Zn(II) Binding Affinity Shed Light on the Mechanisms of Rad50 Hook Domain Functioning and Its Phosphorylation
by Józef Ba Tran, Michał Padjasek and Artur Krężel
Int. J. Mol. Sci. 2022, 23(19), 11140; https://doi.org/10.3390/ijms231911140 - 22 Sep 2022
Cited by 1 | Viewed by 1463
Abstract
The metal binding at protein–protein interfaces is still uncharted territory in intermolecular interactions. To date, only a few protein complexes binding Zn(II) in an intermolecular manner have been deeply investigated. The most notable example of such interfaces is located in the highly conserved [...] Read more.
The metal binding at protein–protein interfaces is still uncharted territory in intermolecular interactions. To date, only a few protein complexes binding Zn(II) in an intermolecular manner have been deeply investigated. The most notable example of such interfaces is located in the highly conserved Rad50 protein, part of the Mre11-Rad50-Nbs1 (MRN) complex, where Zn(II) is required for homodimerization (Zn(Rad50)2). The high stability of Zn(Rad50)2 is conserved not only for the protein derived from the thermophilic archaeon Pyrococcus furiosus (logK12 = 20.95 for 130-amino-acid-long fragment), which was the first one studied, but also for the human paralog studied here (logK12 = 19.52 for a 183-amino-acid-long fragment). As we reported previously, the extremely high stability results from the metal-coupled folding process where particular Rad50 protein fragments play a critical role. The sequence–structure–stability analysis based on human Rad50 presented here separates the individual structural components that increase the stability of the complex, pointing to amino acid residues far away from the Zn(II) binding site as being largely responsible for the complex stabilization. The influence of the individual components is very well reflected by the previously published crystal structure of the human Rad50 zinc hook (PDB: 5GOX). In addition, we hereby report the effect of phosphorylation of the zinc hook domain, which exerts a destabilizing effect on the domain. This study identifies factors governing the stability of metal-mediated protein–protein interactions and illuminates their molecular basis. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions: Recent Advances in Biophysics, Biochemistry, and Bioinformatics)
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