Celerse, F. | bioRxiv Science

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↗

bioRxiv2024

High-resolution Molecular Dynamics Simulations of the Pyruvate Kinase Muscle Isoform 1 and 2 (PKM1/2)

Glucose metabolism plays a pivotal role in physiological processes and cancer growth. The final stage of glycolysis, converting phosphoenolpyruvate (PEP) into pyruvate, is catalyzed by the pyruvate kinase (PK) enzyme. Whereas PKM1 is mainly expressed in cells with high energy requirements, PKM2 is preferentially expressed in proliferating cells, including tumor cells. Structural analysis of PKM1 and PKM2 is essential to design new molecules with antitumoral activity. To understand their structural dynamics, we performed extensive high-resolution molecular dynamics (MD) simulations using adaptive sampling techniques coupled to the polarizable AMOEBA force field. Performing more than 6 {micro}s of simulation, we considered all oligomerization states of PKM2 and propose structural insights for PKM1 to further study the PKM2-specific allostery. We focused on key sites including the active site and the natural substrate Fructose Bi-Phosphate (FBP) fixation pocket. Additionally, we present the first MD simulation of biologically active PKM1 and uncover important similarities with its PKM2 counterpart bound to FBP. We also analysed TEPP-46s fixation, a pharmacological activator binding a different pocket, on PKM2 and highlighted the structural differences and similarities compared to PKM2 bound to FBP. Finally, we determined potential new cryptic pockets specific to PKM2 for drug targeting. Entry for the Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/574528v2_ufig1.gif" ALT="Figure 1"> View larger version (82K): org.highwire.dtl.DTLVardef@1926694org.highwire.dtl.DTLVardef@8cae8aorg.highwire.dtl.DTLVardef@170200org.highwire.dtl.DTLVardef@84760d_HPS_FORMAT_FIGEXP M_FIG C_FIG Producing more than 6{micro}s of cumulated simulation time with the AMOEBA polarizable force field, we determined key structural properties of the PKM2 (catalytic, FBP and TEPP) and PKM1 enzymes binding sites to determine new cryptic pockets for further antiviral/antitumoral drug design.

biophysics↗