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

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 6215

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Special Issue Editor

Dr. Mariapina D'Onofrio

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Guest Editor

Department of Biotechnology, University of Verona, Verona, Italy
Interests: structure; functional interactions; post translational modifications of proteins; NMR spectroscopy; intrinsically disordered proteins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins, an important class of biological macromolecules, realize their functions through binding to themselves or other molecules. Protein–ligand interactions and multi-protein complexes perform central roles in the cellular systems of all living organisms, participating in their activation and regulation (such as transcription and translation, cell–cell adhesion and communication, protein synthesis and degradation, cell cycle control, and signaling cascades).

Protein interactions are also often at the basis of many pathological states. A detailed understanding of the protein–ligand interactions is therefore central to understanding biology at the molecular level and will also facilitate the discovery, design, and development of drugs, including (but not limited to) molecular docking, structure-based design, virtual screening of molecular fragments, small molecules and other types of compounds, clustering of complexes, and structural interpretation of activity cliffs, to name a few.

In this Special Issue of IJMS, we aim to collect contributions in the form of either original research articles or reviews, to add new insight into the role of protein–ligand interactions in biological processes and to highlight the state of the art, the challenges, and the open issues in this varied field of investigation.

Dr. Mariapina D'Onofrio
Guest Editor

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
protein interaction networks
biological processes
protein complexes
molecular recognition

Published Papers (4 papers)

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Research

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15 pages, 6629 KiB

Open AccessArticle

Impacts of Halogen Substitutions on Bisphenol A Compounds Interaction with Human Serum Albumin: Exploring from Spectroscopic Techniques and Computer Simulations

by Huan Zhang, Ruirui Cai, Chaolan Chen, Linna Gao, Pei Ding, Lulu Dai and Baozhu Chi

Int. J. Mol. Sci. 2023, 24(17), 13281; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713281 - 26 Aug 2023

Cited by 1 | Viewed by 1113

Abstract

Bisphenol A (BPA) is an endocrine-disrupting compound, and the binding mechanism of BPA with carrier proteins has drawn widespread attention. Halogen substitutions can significantly impact the properties of BPA, resulting in various effects for human health. Here, we selected tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA) to investigate the interaction between different halogen-substituted BPAs and human serum albumin (HSA). TBBPA/TCBPA spontaneously occupied site I and formed stable binary complexes with HSA. Compared to TCBPA, TBBPA has higher binding affinity to HSA. The effect of different halogen substituents on the negatively charged surface area of BPA was an important reason for the higher binding affinity of TBBPA to HSA compared to TCBPA. Hydrogen bonds and van der Waals forces were crucial in the TCBPA–HSA complex, while the main driving factor for the formation of the TBBPA–HSA complex was hydrophobic interactions. Moreover, the presence of TBBPA/TCBPA changed the secondary structure of HSA. Amino acid residues such as Lys199, Lys195, Phe211, Arg218, His242, Leu481, and Trp214 were found to play crucial roles in the binding process between BPA compounds and HSA. Furthermore, the presence of halogen substituents facilitated the binding of BPA compounds with HSA. Full article

(This article belongs to the Special Issue New Insights into Protein–Ligand Interactions)

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13 pages, 3207 KiB

Open AccessArticle

Potential Clinically Relevant Effects of Sialylation on Human Serum AAG-Drug Interactions Assessed by Isothermal Titration Calorimetry: Insight into Pharmacoglycomics?

by Robert Kerep, Tino Šeba, Valentina Borko, Tin Weitner, Toma Keser, Gordan Lauc and Mario Gabričević

Int. J. Mol. Sci. 2023, 24(10), 8472; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24108472 - 9 May 2023

Cited by 1 | Viewed by 1662

Abstract

Human serum alpha-1 acid glycoprotein is an acute-phase plasma protein involved in the binding and transport of many drugs, especially basic and lipophilic substances. It has been reported that the sialic acid groups that terminate the N–glycan chains of alpha-1 acid glycoprotein change in response to certain health conditions and may have a major impact on drug binding to alpha-1 acid glycoprotein. The interaction between native or desialylated alpha-1 acid glycoprotein and four representative drugs—clindamycin, diltiazem, lidocaine, and warfarin—was quantitatively evaluated using isothermal titration calorimetry. The calorimetry assay used here is a convenient and widely used approach to directly measure the amount of heat released or absorbed during the association processes of biomolecules in solution and to quantitatively estimate the thermodynamics of the interaction. The results showed that the binding of drugs with alpha-1 acid glycoprotein were enthalpy-driven exothermic interactions, and the binding affinity was in the range of 10⁻⁵–10⁻⁶ M. Desialylated alpha-1 acid glycoprotein showed significantly different binding with diltiazem, lidocaine, and warfarin compared with native alpha-1 acid glycoprotein, whereas clindamycin showed no significant difference. Therefore, a different degree of sialylation may result in different binding affinities, and the clinical significance of changes in sialylation or glycosylation of alpha-1 acid glycoprotein in general should not be neglected. Full article

(This article belongs to the Special Issue New Insights into Protein–Ligand Interactions)

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16 pages, 706 KiB

Open AccessArticle

Modeling DTA by Combining Multiple-Instance Learning with a Private-Public Mechanism

by Chunyu Wang, Yuanlong Chen, Lingling Zhao, Junjie Wang and Naifeng Wen

Int. J. Mol. Sci. 2022, 23(19), 11136; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911136 - 22 Sep 2022

Cited by 1 | Viewed by 1356

Abstract

The prediction of the strengths of drug–target interactions, also called drug–target binding affinities (DTA), plays a fundamental role in facilitating drug discovery, where the goal is to find prospective drug candidates. With the increase in the number of drug–protein interactions, machine learning techniques, especially deep learning methods, have become applicable for drug–target interaction discovery because they significantly reduce the required experimental workload. In this paper, we present a spontaneous formulation of the DTA prediction problem as an instance of multi-instance learning. We address the problem in three stages, first organizing given drug and target sequences into instances via a private-public mechanism, then identifying the predicted scores of all instances in the same bag, and finally combining all the predicted scores as the output prediction. A comprehensive evaluation demonstrates that the proposed method outperforms other state-of-the-art methods on three benchmark datasets. Full article

(This article belongs to the Special Issue New Insights into Protein–Ligand Interactions)

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Review

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21 pages, 3072 KiB

Open AccessReview

Protein–Ligand Interactions in Scarcity: The Stringent Response from Bacteria to Metazoa, and the Unanswered Questions

by Sailen Barik

Int. J. Mol. Sci. 2023, 24(4), 3999; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24043999 - 16 Feb 2023

Cited by 1 | Viewed by 1663

Abstract

The stringent response, originally identified in Escherichia coli as a signal that leads to reprogramming of gene expression under starvation or nutrient deprivation, is now recognized as ubiquitous in all bacteria, and also as part of a broader survival strategy in diverse, other stress conditions. Much of our insight into this phenomenon derives from the role of hyperphosphorylated guanosine derivatives (pppGpp, ppGpp, pGpp; guanosine penta-, tetra- and tri-phosphate, respectively) that are synthesized on starvation cues and act as messengers or alarmones. These molecules, collectively referred to here as (p)ppGpp, orchestrate a complex network of biochemical steps that eventually lead to the repression of stable RNA synthesis, growth, and cell division, while promoting amino acid biosynthesis, survival, persistence, and virulence. In this analytical review, we summarize the mechanism of the major signaling pathways in the stringent response, consisting of the synthesis of the (p)ppGpp, their interaction with RNA polymerase, and diverse factors of macromolecular biosynthesis, leading to differential inhibition and activation of specific promoters. We also briefly touch upon the recently reported stringent-like response in a few eukaryotes, which is a very disparate mechanism involving MESH1 (Metazoan SpoT Homolog 1), a cytosolic NADPH phosphatase. Lastly, using ppGpp as an example, we speculate on possible pathways of simultaneous evolution of alarmones and their multiple targets. Full article

(This article belongs to the Special Issue New Insights into Protein–Ligand Interactions)

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