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Protein Structure–Function Relationships 2.0

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 6767

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Dr. Mohammad Hassan Baig

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Department of Family Medicine, Yonsei University College of Medicine, Seoul, Korea
Interests: biotechnology; R statistical package; bioinformatics; molecular biology; molecular dynamics; drug discovery; molecular dynamics simulation; computational chemistry
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Dear Colleagues,

Proteins, the workhorses of the cell, essentially participate in all aspects of living systems. These biopolymers have always been the prime focus of extensive research, aiming to elucidate structure–function relationships. Proteins have a wide range of functions, including signal transduction, ion and nutrient transport, and various other essential processes required for the functioning of biological systems. Understanding the structure–function relationships of proteins is a hot topic, holding great importance in structural biology. The study of the impact of protein mutation, protein interaction with other proteins, and the binding of ligands on protein structure dynamics and function will help to provide valuable insight. Further, structural features are widely exploited in designing and developing small-molecule inhibitors targeting the therapeutic management of various life-threatening diseases. This Issue aims to invite articles focusing on structure–function relationships, drug discovery, evolutionary insights, and structural genomics using combined in silico and experimental methods.

Dr. Mohammad Hassan Baig
Guest Editor

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Keywords

protein–protein interactions
drug design
molecular docking
protein structural dynamics
enzyme functions
QM/MM approaches
virtual screening

Published Papers (4 papers)

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Research

27 pages, 5394 KiB

Open AccessArticle

Inhibitor Trapping in N-Myristoyltransferases as a Mechanism for Drug Potency

by Danislav S. Spassov, Mariyana Atanasova and Irini Doytchinova

Int. J. Mol. Sci. 2023, 24(14), 11610; https://doi.org/10.3390/ijms241411610 - 18 Jul 2023

Cited by 3 | Viewed by 1291

Abstract

Predicting inhibitor potency is critical in drug design and development, yet it has remained one of computational biology’s biggest unresolved challenges. Here, we show that in the case of the N-myristoyltransferase (NMT), this problem could be traced to the mechanisms by which the NMT enzyme is inhibited. NMT adopts open or closed conformations necessary for orchestrating the different steps of the catalytic process. The results indicate that the potency of the NMT inhibitors is determined by their ability to stabilize the enzyme conformation in the closed state, and that in this state, the small molecules themselves are trapped and locked inside the structure of the enzyme, creating a significant barrier for their dissociation. By using molecular dynamics simulations, we demonstrate that the conformational stabilization of the protein molecule in its closed form is highly correlated with the ligands activity and can be used to predict their potency. Hence, predicting inhibitor potency in silico might depend on modeling the conformational changes of the protein molecule upon binding of the ligand rather than estimating the changes in free binding energy that arise from their interaction. Full article

(This article belongs to the Special Issue Protein Structure–Function Relationships 2.0)

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15 pages, 2707 KiB

Open AccessArticle

Proteome-Wide Structural Computations Provide Insights into Empirical Amino Acid Substitution Matrices

by Pablo Aledo and Juan Carlos Aledo

Int. J. Mol. Sci. 2023, 24(1), 796; https://doi.org/10.3390/ijms24010796 - 02 Jan 2023

Cited by 3 | Viewed by 1533

Abstract

The relative contribution of mutation and selection to the amino acid substitution rates observed in empirical matrices is unclear. Herein, we present a neutral continuous fitness-stability model, inspired by the Arrhenius law ( [...] Read more.

q_{i j} = a_{i j} e^{- |Δ Δ G_{i j}|}

). The model postulates that the rate of amino acid substitution (

i \to j

) is determined by the product of a pre-exponential factor, which is influenced by the genetic code structure, and an exponential term reflecting the relative fitness of the amino acid substitutions. To assess the validity of our model, we computed changes in stability of 14,094 proteins, for which 137,073,638 in silico mutants were analyzed. These site-specific data were summarized into a 20 square matrix, whose entries,

|Δ Δ G_{i j}|

, were obtained after averaging through all the sites in all the proteins. We found a significant positive correlation between these energy values and the disease-causing potential of each substitution, suggesting that the exponential term accurately summarizes the fitness effect. A remarkable observation was that amino acids that were highly destabilizing when acting as the source, tended to have little effect when acting as the destination, and vice versa (source

\to

destination). The Arrhenius model accurately reproduced the pattern of substitution rates collected in the empirical matrices, suggesting a relevant role for the genetic code structure and a tuning role for purifying selection exerted via protein stability. Full article

(This article belongs to the Special Issue Protein Structure–Function Relationships 2.0)

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18 pages, 1926 KiB

Open AccessArticle

Synthesis, Biological Activity and Molecular Docking of Chimeric Peptides Targeting Opioid and NOP Receptors

by Karol Wtorek, Alessia Ghidini, Luca Gentilucci, Anna Adamska-Bartłomiejczyk, Justyna Piekielna-Ciesielska, Chiara Ruzza, Chiara Sturaro, Girolamo Calò, Stefano Pieretti, Alicja Kluczyk, John McDonald, David G. Lambert and Anna Janecka

Int. J. Mol. Sci. 2022, 23(20), 12700; https://doi.org/10.3390/ijms232012700 - 21 Oct 2022

Cited by 3 | Viewed by 1926

Abstract

Recently, mixed opioid/NOP agonists came to the spotlight for their favorable functional profiles and promising outcomes in clinical trials as novel analgesics. This study reports on two novel chimeric peptides incorporating the fragment Tyr-c[D-Lys-Phe-Phe]Asp-NH₂ (RP-170), a cyclic peptide with high affinity for µ and κ opioid receptors (or MOP and KOP, respectively), conjugated with the peptide Ac-RYYRIK-NH₂, a known ligand of the nociceptin/orphanin FQ receptor (NOP), yielding RP-170-RYYRIK-NH₂ (KW-495) and RP-170-Gly₃-RYYRIK-NH₂ (KW-496). In vitro, the chimeric KW-496 gained affinity for KOP, hence becoming a dual KOP/MOP agonist, while KW-495 behaved as a mixed MOP/NOP agonist with low nM affinity. Hence, KW-495 was selected for further in vivo experiments. Intrathecal administration of this peptide in mice elicited antinociceptive effects in the hot-plate test; this action was sensitive to both the universal opioid receptor antagonist naloxone and the selective NOP antagonist SB-612111. The rotarod test revealed that KW-495 administration did not alter the mice motor coordination performance. Computational studies have been conducted on the two chimeras to investigate the structural determinants at the basis of the experimental activities, including any role of the Gly₃ spacer. Full article

(This article belongs to the Special Issue Protein Structure–Function Relationships 2.0)

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21 pages, 9835 KiB

Open AccessArticle

The Giardial Arginine Deiminase Participates in Giardia-Host Immunomodulation in a Structure-Dependent Fashion via Toll-like Receptors

by Cynthia Fernández-Lainez, Ignacio de la Mora-de la Mora, Sergio Enríquez-Flores, Itzhel García-Torres, Luis A. Flores-López, Pedro Gutiérrez-Castrellón, Paul de Vos and Gabriel López-Velázquez

Int. J. Mol. Sci. 2022, 23(19), 11552; https://doi.org/10.3390/ijms231911552 - 30 Sep 2022

Cited by 1 | Viewed by 1482

Abstract

Beyond the problem in public health that protist-generated diseases represent, understanding the variety of mechanisms used by these parasites to interact with the human immune system is of biological and medical relevance. Giardia lamblia is an early divergent eukaryotic microorganism showing remarkable pathogenic strategies for evading the immune system of vertebrates. Among various multifunctional proteins in Giardia, arginine deiminase is considered an enzyme that plays multiple regulatory roles during the life cycle of this parasite. One of its most important roles is the crosstalk between the parasite and host. Such a molecular “chat” is mediated in human cells by membrane receptors called Toll-like receptors (TLRs). Here, we studied the importance of the 3D structure of giardial arginine deiminase (GlADI) to immunomodulate the human immune response through TLRs. We demonstrated the direct effect of GlADI on human TLR signaling. We predicted its mode of interaction with TLRs two and four by using the AlphaFold-predicted structure of GlADI and molecular docking. Furthermore, we showed that the immunomodulatory capacity of this virulent factor of Giardia depends on the maintenance of its 3D structure. Finally, we also showed the influence of this enzyme to exert specific responses on infant-like dendritic cells. Full article

(This article belongs to the Special Issue Protein Structure–Function Relationships 2.0)

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