International Journal of Molecular Sciences

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14 pages, 1978 KiB

Open AccessArticle

by Markus Meringer, Gerardo M. Casanola-Martin, Bakhtiyor Rasulev and H. James Cleaves II

Int. J. Mol. Sci. 2024, 25(22), 12343; https://doi.org/10.3390/ijms252212343 - 17 Nov 2024

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Many non-natural amino acids can be incorporated by biological systems into coded functional peptides and proteins. For such incorporations to be effective, they must not only be compatible with the desired function but also evade various biochemical error-checking mechanisms. The underlying molecular mechanisms [...] Read more.

Many non-natural amino acids can be incorporated by biological systems into coded functional peptides and proteins. For such incorporations to be effective, they must not only be compatible with the desired function but also evade various biochemical error-checking mechanisms. The underlying molecular mechanisms are complex, and this problem has been approached previously largely by expert perception of isomer compatibility, followed by empirical study. However, the number of amino acids that might be incorporable by the biological coding machinery may be too large to survey efficiently using such an intuitive approach. We introduce here a workflow for searching real and computed non-natural amino acid libraries for biosimilar amino acids which may be incorporable into coded proteins with minimal unintended disturbance of function. This workflow was also applied to molecules which have been previously benchmarked for their compatibility with the biological translation apparatus, as well as commercial catalogs. We report the results of scoring their contents based on fingerprint similarity via Tanimoto coefficients. These similarity scoring methods reveal candidate amino acids which could be substitutable into modern proteins. Our analysis discovers some already-implemented substitutions, but also suggests many novel ones. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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18 pages, 8171 KiB

Open AccessArticle

The Trajectory of Damaged-Base Eversion into the Active Site of Apurinic/Apyrimidinic Endonuclease APE1 Regulates This Enzyme’s Substrate Specificity

by Anatoly A. Bulygin and Nikita A. Kuznetsov

Int. J. Mol. Sci. 2024, 25(22), 12287; https://doi.org/10.3390/ijms252212287 - 15 Nov 2024

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Abstract

Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for the hydrolysis of the phosphodiester bond on the 5′ side of an apurinic/apyrimidinic site during base excision repair. Moreover, in DNA, this enzyme can recognize nucleotides containing such damaged bases as 5,6-dihydro-2′-deoxyuridine (DHU), 2′-deoxyuridine (dU), alpha-2′-deoxyadenosine [...] Read more.

Apurinic/apyrimidinic endonuclease 1 (APE1) is responsible for the hydrolysis of the phosphodiester bond on the 5′ side of an apurinic/apyrimidinic site during base excision repair. Moreover, in DNA, this enzyme can recognize nucleotides containing such damaged bases as 5,6-dihydro-2′-deoxyuridine (DHU), 2′-deoxyuridine (dU), alpha-2′-deoxyadenosine (αA), and 1,N6-ethenoadenosine (εA). Previously, by pulsed electron–electron double resonance spectroscopy and pre-steady-state kinetic analysis, we have revealed multistep DNA rearrangements during the formation of the catalytic complex. In the present study, the modeling of the eversion trajectory of nucleotides with various damaged bases was performed by directed molecular dynamics simulations. It was found that each damaged base at the beginning of the eversion interacts with protein loop Val196-Arg201, which should be moved to enable further nucleotide eversion. This movement involves a shift in loop Val196-Arg201 away from loop Asn253-Thr257 and requires the disruption of contacts between these loops. The Glu260Ala substitution facilitates the separation of the two loops. Moreover, conformational changes in the Asn253-Thr257 loop should occur in the second half of the lesion eversion trajectory. All these perturbations within the protein globule tend to reduce steric interactions of each damaged base with the protein during the eversion of the nucleotide from DNA and movement to the active site. These perturbations are important determinants of substrate specificity of endonuclease APE1. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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24 pages, 6571 KiB

Open AccessArticle

Deciphering the Impact of Nucleosides and Nucleotides on Copper Ion and Dopamine Coordination Dynamics

by Patrycja Sadowska, Wojciech Jankowski, Romualda Bregier-Jarzębowska, Piotr Pietrzyk and Renata Jastrząb

Int. J. Mol. Sci. 2024, 25(17), 9137; https://doi.org/10.3390/ijms25179137 - 23 Aug 2024

Cited by 1 | Viewed by 941

Abstract

The mode of coordination of copper(II) ions with dopamine (DA, L) in the binary, as well as ternary systems with Ado, AMP, ADP, and ATP (L′) as second ligands, was studied with the use of experimental—potentiometric and spectroscopic (VIS, EPR, NMR, IR)—methods and [...] Read more.

The mode of coordination of copper(II) ions with dopamine (DA, L) in the binary, as well as ternary systems with Ado, AMP, ADP, and ATP (L′) as second ligands, was studied with the use of experimental—potentiometric and spectroscopic (VIS, EPR, NMR, IR)—methods and computational—molecular modeling and DFT—studies. In the Cu(II)/DA system, depending on the pH value, the active centers of the ligand involved in the coordination with copper(II) ions changed from nitrogen and oxygen atoms (CuH(DA)³⁺, Cu(DA)²⁺), via nitrogen atoms (CuH₂(DA)₂⁴⁺), to oxygen atoms at strongly alkaline pH (Cu(DA)₂²⁺). The introduction of L′ into this system changed the mode of interaction of dopamine from oxygen atoms to the nitrogen atom in the hydroxocomplexes formed at high pH values. In the ternary systems, the ML′-L (non-covalent interaction) and ML′HxL, ML′L, and ML′L(OH)x species were found. In the Cu(II)/DA/AMP or ATP systems, mixed forms were formed up to a pH of around 9.0; above this pH, only Cu(II)/DA complexes occurred. In contrast to systems with AMP and ATP, ternary species with Ado and ADP occurred in the whole pH range at a high concentration, and moreover, binary complexes of Cu(II) ions with dopamine did not form in the detectable concentration. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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22 pages, 5849 KiB

Open AccessArticle

Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin–Sulfonamide–Nitroindazolyl–Triazole Hybrids as Monoamine Oxidase Inhibitors

by Mohammed Eddahmi, Gabriella La Spada, Luis R. Domingo, Gérard Vergoten, Christian Bailly, Marco Catto and Latifa Bouissane

Int. J. Mol. Sci. 2024, 25(12), 6803; https://doi.org/10.3390/ijms25126803 - 20 Jun 2024

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Abstract

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed [...] Read more.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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14 pages, 2277 KiB

Open AccessArticle

Structure–Activity Relationship Models to Predict Properties of the Dielectric Fluids for Transformer Insulation System

by Mi Zhang, Hua Hou and Baoshan Wang

Int. J. Mol. Sci. 2024, 25(12), 6654; https://doi.org/10.3390/ijms25126654 - 17 Jun 2024

Cited by 1 | Viewed by 1106

Abstract

Mineral oils and synthetic and natural esters are the predominant insulating liquids in electrical equipment. Structure–activity relationship models to predict the key properties of pure insulating liquids, including pulse breakdown strengths, AC breakdown voltages, dielectric constants, flash points, and kinematic viscosities, have been [...] Read more.

Mineral oils and synthetic and natural esters are the predominant insulating liquids in electrical equipment. Structure–activity relationship models to predict the key properties of pure insulating liquids, including pulse breakdown strengths, AC breakdown voltages, dielectric constants, flash points, and kinematic viscosities, have been proposed for the first time. Dependence of the specific properties on the molecular structures has been illustrated quantitatively in terms of surface area, statistical total variance, and average deviation of positive and negative electrostatic potentials, as augmented by molecular weight, volume, and ovality. Moreover, the individual contribution of the functional groups to viscosity has been revealed by an additive approach. The predicted properties are in good agreement with the experimental data. The present theoretical work provides new insights on the development of novel dielectric fluids. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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20 pages, 8140 KiB

Open AccessArticle

TATA-Binding Protein-Based Virtual Screening of FDA Drugs Identified New Anti-Giardiasis Agents

by Carlos Gaona-López, Domingo Méndez-Álvarez, Adriana Moreno-Rodríguez, Juan Luis Bautista-Martínez, José Antonio De Fuentes-Vicente, Benjamín Nogueda-Torres, Itzhel García-Torres, Gabriel López-Velázquez and Gildardo Rivera

Int. J. Mol. Sci. 2024, 25(11), 6238; https://doi.org/10.3390/ijms25116238 - 5 Jun 2024

Cited by 1 | Viewed by 1313

Abstract

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research [...] Read more.

Parasitic diseases, predominantly prevalent in developing countries, are increasingly spreading to high-income nations due to shifting migration patterns. The World Health Organization (WHO) estimates approximately 300 million annual cases of giardiasis. The emergence of drug resistance and associated side effects necessitates urgent research to address this growing health concern. In this study, we evaluated over eleven thousand pharmacological compounds sourced from the FDA database to assess their impact on the TATA-binding protein (TBP) of the early diverging protist Giardia lamblia, which holds medical significance. We identified a selection of potential pharmacological compounds for combating this parasitic disease through in silico analysis, employing molecular modeling techniques such as homology modeling, molecular docking, and molecular dynamics simulations. Notably, our findings highlight compounds DB07352 and DB08399 as promising candidates for inhibiting the TBP of Giardia lamblia. Also, these compounds and DB15584 demonstrated high efficacy against trophozoites in vitro. In summary, this study identifies compounds with the potential to combat giardiasis, offering the prospect of specific therapies and providing a robust foundation for future research. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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14 pages, 1292 KiB

Open AccessArticle

TumFlow: An AI Model for Predicting New Anticancer Molecules

by Davide Rigoni, Sachithra Yaddehige, Nicoletta Bianchi, Alessandro Sperduti, Stefano Moro and Cristian Taccioli

Int. J. Mol. Sci. 2024, 25(11), 6186; https://doi.org/10.3390/ijms25116186 - 4 Jun 2024

Cited by 2 | Viewed by 1816

Abstract

Melanoma is the fifth most common cancer in the United States. Conventional drug discovery methods are inherently time-consuming and costly, which imposes significant limitations. However, the advent of Artificial Intelligence (AI) has opened up new possibilities for simulating and evaluating numerous drug candidates, [...] Read more.

Melanoma is the fifth most common cancer in the United States. Conventional drug discovery methods are inherently time-consuming and costly, which imposes significant limitations. However, the advent of Artificial Intelligence (AI) has opened up new possibilities for simulating and evaluating numerous drug candidates, thereby mitigating the requisite time and resources. In this context, normalizing flow models by employing machine learning techniques to create new molecular structures holds promise for accelerating the discovery of effective anticancer therapies. This manuscript introduces TumFlow, a novel AI model designed to generate new molecular entities with potential therapeutic value in cancer treatment. It has been trained on the NCI-60 dataset, encompassing thousands of molecules tested across 60 tumour cell lines, with an emphasis on the melanoma SK-MEL-28 cell line. The model successfully generated new molecules with predicted improved efficacy in inhibiting tumour growth while being synthetically feasible. This represents a significant advancement over conventional generative models, which often produce molecules that are challenging or impossible to synthesize. Furthermore, TumFlow has also been utilized to optimize molecules known for their efficacy in clinical melanoma treatments. This led to the creation of novel molecules with a predicted enhanced likelihood of effectiveness against melanoma, currently undocumented on PubChem. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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23 pages, 3142 KiB

Open AccessArticle

ARIP: A Tool for Precise Interatomic Contact Area and Volume Calculation in Proteins

by Tao Ma, Wenhui Li, Zhiping Tang, Xiangwei Sun, Lijuan Li, Zhonghua Liu and Gaihua Zhang

Int. J. Mol. Sci. 2024, 25(10), 5176; https://doi.org/10.3390/ijms25105176 - 9 May 2024

Viewed by 2055

Abstract

The interplay patterns of amino acid residues are pivotal in determining the tertiary structure and flexibility of proteins, which in turn are intricately linked to their functionality and interactions with other molecules. Here, we introduce ARIP, a novel tool designed to identify contact [...] Read more.

The interplay patterns of amino acid residues are pivotal in determining the tertiary structure and flexibility of proteins, which in turn are intricately linked to their functionality and interactions with other molecules. Here, we introduce ARIP, a novel tool designed to identify contact residues within proteins. ARIP employs a modified version of the dr_sasa algorithm and an atomic overlap weighted algorithm to directly calculate the contact area and volume between atoms based on their van der Waals radius. It also allows for the selection of solvent radii, recognizing that not every atom in proteins can interact with water molecules. The solvent parameters were derived from the analysis of approximately 5000 protein and nucleic acid structures with water molecules determined using X-ray crystallography. One advantage of the modified algorithm is its capability to analyze multiple models within a single PDB file, making it suitable for molecular dynamic capture. The contact volume is symmetrically distributed between the interacting atoms, providing more informative results than contact area for the analysis of intra- and intermolecular interactions and the development of scoring functions. Furthermore, ARIP has been applied to four distinct cases: capturing key residue–residue contacts in NMR structures of P4HB, protein–drug binding of CYP17A1, protein–DNA binding of SPI1, and molecular dynamic simulations of BRD4. Full article

(This article belongs to the Special Issue Computational Approaches for the Investigation of Complex Molecular Mechanisms, 3rd Edition)

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