دورية أكاديمية
أعرض في EDS

Multilayered Computational Framework for Designing Peptide Inhibitors of HVEM-LIGHT Interaction.

التفاصيل البيبلوغرافية
العنوان: Multilayered Computational Framework for Designing Peptide Inhibitors of HVEM-LIGHT Interaction.
المؤلفون: Ciura P; Faculty of Chemistry, Fahrenheit Union of Universities in Gdańsk, University of Gdańsk, Baż̇yńskiego 8, 80-309 Gdansḱ, Poland., Smardz P; Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland., Spodzieja M; Faculty of Chemistry, Fahrenheit Union of Universities in Gdańsk, University of Gdańsk, Baż̇yńskiego 8, 80-309 Gdansḱ, Poland., Sieradzan AK; Faculty of Chemistry, Fahrenheit Union of Universities in Gdańsk, University of Gdańsk, Baż̇yńskiego 8, 80-309 Gdansḱ, Poland., Krupa P; Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland.
المصدر: The journal of physical chemistry. B [J Phys Chem B] 2024 Jul 18; Vol. 128 (28), pp. 6770-6785. Date of Electronic Publication: 2024 Jul 03.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101157530 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5207 (Electronic) Linking ISSN: 15205207 NLM ISO Abbreviation: J Phys Chem B Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c1997-
مواضيع طبية MeSH: Molecular Dynamics Simulation* , Peptides*/chemistry , Peptides*/metabolism , Peptides*/pharmacology , Receptors, Tumor Necrosis Factor, Member 14*/chemistry , Receptors, Tumor Necrosis Factor, Member 14*/metabolism , Protein Binding*, Humans ; Tumor Necrosis Factor Ligand Superfamily Member 14/chemistry ; Tumor Necrosis Factor Ligand Superfamily Member 14/metabolism ; Drug Design ; Amino Acid Sequence ; Thermodynamics
مستخلص: The herpesvirus entry mediator (HVEM) and its ligand LIGHT play crucial roles in immune system regulation, including T-cell proliferation, B-cell differentiation, and immunoglobulin secretion. However, excessive T-cell activation can lead to chronic inflammation and autoimmune diseases. Thus, inhibiting the HVEM-LIGHT interaction emerges as a promising therapeutic strategy for these conditions and in preventing adverse reactions in organ transplantation. This study focused on designing peptide inhibitors, targeting the HVEM-LIGHT interaction, using molecular dynamics (MD) simulations of 65 peptides derived from HVEM. These peptides varied in length and disulfide-bond configurations, crucial for their interaction with the LIGHT trimer. By simulating 31 HVEM domain variants, including the full-length protein, we assessed conformational changes upon LIGHT binding to understand the influence of HVEM segments and disulfide bonds on the binding mechanism. Employing multitrajectory microsecond-scale, all-atom MD simulations and molecular mechanics with generalized Born and surface area (MM-GBSA) binding energy estimation, we identified promising CRD2 domain variants with high LIGHT affinity. Notably, point mutations in these variants led to a peptide with a single disulfide bond (C58-C73) and a K54E substitution, exhibiting the highest binding affinity. The importance of the CRD2 domain and Cys58-Cys73 disulfide bond for interrupting HVEM-LIGHT interaction was further supported by analyzing truncated CRD2 variants, demonstrating similar binding strengths and mechanisms. Further investigations into the binding mechanism utilized steered MD simulations at various pulling speeds and umbrella sampling to estimate the energy profile of HVEM-based inhibitors with LIGHT. These comprehensive analyses revealed key interactions and different binding mechanisms, highlighting the increased binding affinity of selected peptide variants. Experimental circular dichroism techniques confirmed the structural properties of these variants. This study not only advances our understanding of the molecular basis of HVEM-LIGHT interactions but also provides a foundation for developing novel therapeutic strategies for immune-related disorders. Furthermore, it sets a gold standard for peptide inhibitor design in drug development due to its systematic approach.
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المشرفين على المادة: 0 (Peptides)
0 (Receptors, Tumor Necrosis Factor, Member 14)
0 (Tumor Necrosis Factor Ligand Superfamily Member 14)
0 (TNFSF14 protein, human)
تواريخ الأحداث: Date Created: 20240703 Date Completed: 20240718 Latest Revision: 20240808
رمز التحديث: 20240808
مُعرف محوري في PubMed: PMC11264271
DOI: 10.1021/acs.jpcb.4c02255
PMID: 38958133
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-5207
DOI:10.1021/acs.jpcb.4c02255