2024/08/29 by Dina El Ahdab, Louis Lagardère, Zeina Hobaika +5 · 1 voice
Biochemistry, Genetics and Molecular Biology · #DNA and Nucleic Acid Chemistry #Advanced biosensing and bioanalysis techniques #RNA Interference and Gene Delivery
paper · pdf · doi:10.1101/2024.08.28.610081
openalex publication_date 2024/08/29 · openalex created_date 2024/08/30 · openalex updated_date 2026/07/22
Abstract Long oligomer sequences, rich in guanine and cytosine, such as c-kit1 and the HIV-1 LTR-III sequence, are prevalent in oncogenes and retroviruses and play crucial roles in cancer. Understanding the conformational dynamics of such guanine quadruplexes and identifying druggable regions are therefore essential for developing new inhibition strategies. In this study, we used extensive AMOEBA polarizable force field molecular dynamics simulations combined with data-driven adaptive sampling and clustering algorithms, reaching a cumulative simulation time of 7.5 µ s for c-kit1 . Such simulations identified novel structural motives and show-cased the flexible loop dynamics, as well as the role of polarizable water in transient stabilization of the G-quadruplex. They also identified two druggable pockets in c-kit1 . The 400 ns simulation of the HIV-1 LTR-III sequence confirmed its quadruplex stability and uncovered a potentially druggable cryptic pocket.