Investigating pH-induced conformational switch in PIM-1: An integrated multi spectroscopic and MD simulation study

Aanchal Rathi; Saba Noor; Shama Khan; Faizya Khan; Farah Anjum; Anam Ashraf; Aaliya Taiyab; Asimul Islam; Md Imtaiyaz Hassan; Mohammad Mahfuzul Haque

doi:10.1016/j.compbiolchem.2024.108265

Investigating pH-induced conformational switch in PIM-1: An integrated multi spectroscopic and MD simulation study

Comput Biol Chem. 2024 Oct 28:113:108265. doi: 10.1016/j.compbiolchem.2024.108265. Online ahead of print.

Authors

Affiliations

¹ Department of Biotechnology, Faculty of Life Sciences, Jamia Millia Islamia, New Delhi 110025, India.
² Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India.
³ South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, University of the Witwatersrand, Faculty of Health Science, Johannesburg, South Africa.
⁴ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, PO Box 11099, Taif 21944, Saudi Arabia.
⁵ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India. Electronic address: mihassan@jmi.ac.in.
⁶ Department of Biotechnology, Faculty of Life Sciences, Jamia Millia Islamia, New Delhi 110025, India. Electronic address: mhaque@jmi.ac.in.

PMID: 39488934
DOI: 10.1016/j.compbiolchem.2024.108265

Abstract

PIM-1 is a Ser/Thr kinase, which has been extensively studied as a potential target for cancer therapy due to its significant roles in various cancers, including prostate and breast cancers. Given its importance in cancer, researchers are investigating the structure of PIM-1 for pharmacological inhibition to discover therapeutic intervention. This study examines structural and conformational changes in PIM-1 across different pH using various spectroscopic and computational techniques. Spectroscopic results indicate that PIM-1 maintains its secondary and tertiary structure within the pH range of 7.0-9.0. However, protein aggregation occurs in the acidic pH range of 5.0-6.0. Additionally, kinase assays suggested that PIM-1 activity is optimal within the pH range of 7.0-9.0. Subsequently, we performed a 100 ns all-atom molecular dynamics (MD) simulation to see the effect of pH on PIM-1 structural stability at the molecular level. MD simulation analysis revealed that PIM-1 retains its native conformation in alkaline conditions, with some residual fluctuations in acidic conditions as well. A strong correlation was observed between our MD simulation, spectroscopic, and enzymatic activity studies. Understanding the pH-dependent structural changes of PIM-1 can provide insights into its role in disease conditions and cellular homeostasis, particularly regarding protein function under varying pH conditions.

Keywords: Breast cancer; Conformational dynamics; MD simulation; PIM-1 kinase; Prostate cancer; Structure-function relationship; pH-induced denaturation.