Your browser doesn't support javascript.
loading
Natural compound plumbagin based inhibition of hIAPP revealed by Markov state models based on MD data along with experimental validations.
Nabi, Faisal; Ahmad, Owais; Khan, Adeeba; Hassan, Md Nadir; Hisamuddin, Malik; Malik, Sadia; Chaari, Ali; Khan, Rizwan Hasan.
Afiliação
  • Nabi F; Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
  • Ahmad O; Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
  • Khan A; Zakir Hussain College of Engineering and Technology, Aligarh Muslim University, Aligarh, India.
  • Hassan MN; Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
  • Hisamuddin M; Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
  • Malik S; Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
  • Chaari A; Premedical Division, Weill Cornell Medicine Qatar, Qatar Foundation, Doha, Qatar.
  • Khan RH; Interdisciplinary Biotechnology Unit, Aligarh Muslim University, Aligarh, India.
Proteins ; 92(9): 1070-1084, 2024 Sep.
Article em En | MEDLINE | ID: mdl-38497314
ABSTRACT
Human islet amyloid polypeptide (amylin or hIAPP) is a 37 residue hormone co-secreted with insulin from ß cells of the pancreas. In patients suffering from type-2 diabetes, amylin self-assembles into amyloid fibrils, ultimately leading to the death of the pancreatic cells. However, a research gap exists in preventing and treating such amyloidosis. Plumbagin, a natural compound, has previously been demonstrated to have inhibitory potential against insulin amyloidosis. Our investigation unveils collapsible regions within hIAPP that, upon collapse, facilitates hydrophobic and pi-pi interactions, ultimately leading to aggregation. Intriguingly plumbagin exhibits the ability to bind these specific collapsible regions, thereby impeding the aforementioned interactions that would otherwise drive hIAPP aggregation. We have used atomistic molecular dynamics approach to determine secondary structural changes. MSM shows metastable states forming native like hIAPP structure in presence of PGN. Our in silico results concur with in vitro results. The ThT assay revealed a striking 50% decrease in fluorescence intensity at a 11 ratio of hIAPP to Plumbagin. This finding suggests a significant inhibition of amyloid fibril formation by plumbagin, as ThT fluorescence directly correlates with the presence of these fibrils. Further TEM images revealed disappearance of hIAPP fibrils in plumbagin pre-treated hIAPP samples. Also, we have shown that plumbagin disrupts the intermolecular hydrogen bonding in hIAPP fibrils leading to an increase in the average beta strand spacing, thereby causing disaggregation of pre-formed fibrils demonstrating overall disruption of the aggregation machinery of hIAPP. Our work is the first to report a detailed atomistic simulation of 22 µs for hIAPP. Overall, our studies put plumbagin as a potential candidate for both preventive and therapeutic candidate for hIAPP amyloidosis.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Naftoquinonas / Simulação de Dinâmica Molecular / Polipeptídeo Amiloide das Ilhotas Pancreáticas Limite: Humans Idioma: En Revista: Proteins Assunto da revista: BIOQUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Índia País de publicação: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Naftoquinonas / Simulação de Dinâmica Molecular / Polipeptídeo Amiloide das Ilhotas Pancreáticas Limite: Humans Idioma: En Revista: Proteins Assunto da revista: BIOQUIMICA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Índia País de publicação: EEUU / ESTADOS UNIDOS / ESTADOS UNIDOS DA AMERICA / EUA / UNITED STATES / UNITED STATES OF AMERICA / US / USA