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Special Issue "Advances in Molecular Modeling, Docking and Simulations of Protein Structure"

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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: 31 December 2023 | Viewed by 2402

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Dr. Lorant Janosi

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Molecular and Biomolecular Physics Department, National Institute for Research and Development of Isotopic and Molecular Technologies, 65-103 Donath Street, 400293 Cluj-Napoca, Romania
Interests: molecular modeling; peptide design; protein structure; transmembrane channel and protein; oncogenic proteins; potential of mean force

Special Issue Information

Dear Colleagues,

Molecular modeling has been used for decades as a support for or in combination with experimental results. Most in silico experiments in this area have cover the nano-, micro-, and recently meso-scale events/phenomena/mechanisms of interest.

This Special Issue of IJMS aims to compile original research articles or novel communications that address the use of molecular modeling, molecular docking and computer simulations in the context of their predictive power/essential contribution in: (i) identifying novel aspects of molecular mechanisms/structure–activity relationships within protein complexes (e.g. looking into protein associations); (ii) analyses/predictions of protein/peptide structures (e.g. peptides’ structural transitions/pathways); (iii) understanding interactions in protein complexes (e.g. determining ligand/protein–protein binding sites/affinities); (iv) designing novel protein-binding ligands/peptides (e.g. design of novel anti-microbial/anti-cancer peptides), etc.

Works should utilize computational tools such as molecular dynamics simulations (in all their varieties), molecular docking, Monte Carlo methods, molecular modeling methods, QM/MM, etc. Researchers are encouraged to develop symbiotic relationships with experimental results.

Systems simulated/analyzed should include amino acid-based proteins or peptides. The study of complexes with DNA/RNA/lipids/ligands, etc., is also encouraged.

Dr. Lorant Janosi
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

molecular modeling
protein structure
molecular mechanisms
protein interactomics
ligand design
peptides
molecular dynamics
molecular docking

Published Papers (3 papers)

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Research

19 pages, 4648 KiB

Open AccessArticle

Unveiling the Anti-Cancer Potential of Onoceranoid Triterpenes from Lansium domesticum Corr. cv. kokosan: An In Silico Study against Estrogen Receptor Alpha

Ari Hardianto

Sarah Syifa Mardetia

Wanda Destiarani

Yudha Prawira Budiman

Dikdik Kurnia

and

Tri Mayanti

Int. J. Mol. Sci. 2023, 24(19), 15033; https://doi.org/10.3390/ijms241915033 - 09 Oct 2023

Viewed by 692

Abstract

Breast cancer is a significant global concern, with tamoxifen, the standard treatment, raising long-term safety issues due to side effects. In this study, we evaluated the potential of five onoceranoid triterpenes from Lansium domesticum Corr. cv. kokosan against estrogen receptor alpha (ERα) using in silico techniques. Utilizing molecular docking, Lipinski’s rule of five, in silico ADMET, and molecular dynamics simulations, we assessed the potency of five onoceranoid triterpenes against ERα. Molecular docking indicated competitive binding energies for these triterpenes relative to the active form of tamoxifen (4OHT) and estradiol, an ERα native ligand. Three triterpenes met drug-likeness criteria with favorable ADMET profiles. Notably, 2 demonstrated superior binding affinity in molecular dynamics simulations, outperforming estradiol, closely followed by 3 and 4. Hierarchical clustering on principal components (HCPC) and the spatial distribution of contact surface area (CSA) analyses suggest that these triterpenes, especially 2, may act as antagonist ligands akin to 4OHT. These findings highlight the potential of onoceranoid triterpenes in treating ERα-related breast cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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33 pages, 7764 KiB

Open AccessArticle

Interaction of Synthetic Cannabinoid Receptor Agonists with Cannabinoid Receptor I: Insights into Activation Molecular Mechanism

Sergei Gavryushov

Anton Bashilov

Konstantin V. Cherashev-Tumanov

Nikolay N. Kuzmich

Tatyana I. Burykina

and

Boris N. Izotov

Int. J. Mol. Sci. 2023, 24(19), 14874; https://doi.org/10.3390/ijms241914874 - 03 Oct 2023

Viewed by 672

Abstract

Synthetic cannabinoid receptor agonists (SCRAs) have become a wide group of new psychoactive substances since the 2010s. For the last few years, the X-ray structures of the complexes of cannabinoid receptor I (CB₁) with SCRAs as well as the complexes of CB₁ with its antagonist have been published. Based on those data, SCRA–CB₁ interactions are analyzed in detail, using molecular modeling and molecular dynamics simulations. The molecular mechanism of the conformational transformation of the transmembrane domain of CB₁ caused by its interaction with SCRA is studied. These conformational changes allosterically modulate the CB₁–G_i complex, providing activation of the G_i protein. Based on the X-ray-determined structures of the CB₁–ligand complexes, a stable apo conformation of inactive CB₁ with a relatively low potential barrier of receptor activation was modeled. For that model, molecular dynamic simulations of SCRA binding to CB₁ led to the active state of CB₁, which allowed us to explore the key features of this activation and the molecular mechanism of the receptor’s structural transformation. The simulated CB₁ activation is in accordance with the previously published experimental data for the activation at protein mutations or structural changes of ligands. The key feature of the suggested activation mechanism is the determination of the stiff core of the CB₁ transmembrane domain and the statement that the entire conformational transformation of the receptor to the active state is caused by a shift of alpha helix TM7 relative to this core. The shift itself is caused by protein–ligand interactions. It was verified via steered molecular dynamics simulations of the X-ray-determined structures of the inactive receptor, which resulted in the active conformation of CB₁ irrespective of the placement of agonist ligand in the receptor’s active site. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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17 pages, 8880 KiB

Open AccessArticle

Molecular Mechanism of Mutational Disruption of DCLK1 Autoinhibition Provides a Rationale for Inhibitor Screening

and

Int. J. Mol. Sci. 2023, 24(18), 14020; https://doi.org/10.3390/ijms241814020 - 13 Sep 2023

Viewed by 510

Abstract

Doublecortin-like kinase 1 (DCLK1) is a prominent kinase involved in carcinogenesis, serving as a diagnostic marker for early cancer detection and prevention, as well as a target for cancer therapy. Extensive research efforts have been dedicated to understanding its role in cancer development and designing selective inhibitors. In our previous work, we successfully determined the crystal structure of DCLK1 while it was bound to its autoinhibitory domain (AID) at the active site. By analyzing this structure, we were able to uncover the intricate molecular mechanisms behind specific cancer-causing mutations in DCLK1. Utilizing molecular dynamics simulations, we discovered that these mutations disrupt the smooth assembly of the AID, particularly affecting the R2 helix, into the kinase domain (KD). This disruption leads to the exposure of the D533 residue of the DFG (Asp-Phe-Gly) motif in the KD, either through steric hindrance, the rearrangement of electrostatic interactions, or the disruption of local structures in the AID. With these molecular insights, we conducted a screening process to identify potential small-molecule inhibitors that could bind to DCLK1 through an alternative binding mode. To assess the binding affinity of these inhibitors to the KD of DCLK1, we performed calculations on their binding energy and conducted SPR experiments. We anticipate that our study will contribute novel perspectives to the field of drug screening and optimization, particularly in targeting DCLK1. Full article

(This article belongs to the Special Issue Advances in Molecular Modeling, Docking and Simulations of Protein Structure)

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Special Issue "Advances in Molecular Modeling, Docking and Simulations of Protein Structure"

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