Gresh, N. | Search bioRxiv

bioRxiv2024

AMOEBA Polarizable Molecular Dynamics Simulations of Guanine Quadruplexes: from the c-Kit Proto-oncogene to HIV-1

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 {micro}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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/610081v4_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@109a0b4org.highwire.dtl.DTLVardef@115afe8org.highwire.dtl.DTLVardef@cfdc30org.highwire.dtl.DTLVardef@810e33_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Enforcing local DNA kinks by sequence-selective trisintercalating oligopeptides of a tricationic porphyrin. A polarizable Molecular Dynamics study.

Bisacridinyl-bisarginyl porphyrin (BABAP) is a trisintercalating derivative of a tricationic porphyrin, formerly designed and synthesized in order to selectively target and photosensitize the ten-base pair palindromic sequence d(CGGGCGCCCG)2. We resorted to the previously derived (Far et al., 2004) lowest energy-minimized (EM) structure of the BABAP complex with this sequence as a starting point. We performed polarizable molecular dynamics (MD) on this complex. It showed, over a 150 ns duration, the persistent binding of the Arg side-chain on each BABAP arm to the two G bases upstream from the central porphyrin intercalation site. We subsequently performed progressive shortenings of the connector chain linking the Arg-Gly backbone to the acridine, from n=6 methylenes to 4, followed by removal of the Gly backbone and further connector shortenings, from n=4 to n=1. These resulted into progressive deformations ( kinks) of the DNA backbone. In its most accented kinked structure, the DNA backbone was found to have a close overlap with that of DNA bound to Cre recombinase, with, at the level of one acridine intercalation site, negative roll and positive tilt values consistent with those experimentally found for this DNA at its own kinked dinucleotide sequence. Thus, in addition to their photosensitizing properties, some BABAP derivatives could induce sequence-selective, controlled DNA deformations, which are targets for cleavage by endonucleases or for repair enzymes.

biophysics↗