Biology subjects

Piquemal, J.-P.

Publications and source records attributed to Piquemal, J.-P..

6 recordsLinked to original sources

bioRxiv2025

Satellite Tobacco Mosaic Virus: Revealing Environmental Drivers of Capsid and Nucleocapsid Stability using High-Resolution Simulations

The Satellite Tobacco Mosaic Virus (STMV) serves as a model system for elucidating how electrostatic and mechanical forces shape single-stranded (ss) RNA viral architecture. Lever-aging a cumulative total of 1.5 {micro}s of simulation with a polarizable force field including 1.2 {micro}s of conventional Molecular Dynamics (MD) supplemented by Gaussian accelerated MD (GaMD), and well-tempered metadynamics (WTMetaD) enhanced sampling techniques, we examined how pH and ionic composition regulate the structural dynamics of preassembled STMV capsids. Six [~]1M-atom assemblies spanning physiological and stress-mimicking environments were modeled to capture the interplay among protein-protein, protein-RNA, and ion-mediated interactions. A representative GaMD trajectory, corresponding to the up to {micro}s-equivalent regime of conventional MD, revealed that the capsid undergoes coordinated radial fluctuations, with collective expansion and contraction of the icosahedral shell. WTMetaD free-energy surfaces, computed for all six assemblies, delineated distinct condition-specific minima, defining thermodynamically accessible conformations for each environment. During the early relaxation dynamics revealed in conventional MD, RNA-free capsids preserved their icosahedral symmetry in physiological salt, where monovalent ions screened intra-capsid electrostatics. RNA encapsidation further modulated this balance through divalent-ion coordination at the protein-RNA interface. Under acidic conditions, a reversible Na+/Mg2+ exchange reorganized interfacial charge networks while maintaining the overall capsid architecture. Transient chloride binding intermittently disrupted key inter-monomer salt bridges, exposing a regulatory mechanism for capsid plasticity and permeability. Our findings establish STMV as an inherently dynamic, ion-responsive structural assembly whose conformational adaptability emerges from finely balanced electrostatic coupling between the capsid and its RNA, providing an atomistic framework for how ssRNA icosahedral viruses sense and adjust to environmental changes.

biophysics↗

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

Water-Glycan Interactions Drive the SARS-CoV-2 Spike Dynamics: Insights into Glycan-Gate Control and Camouflage Mechanism

To develop therapeutic strategies against COVID-19, we introduce a high-resolution all-atom polarizable model capturing many-body effects of protein, glycans, solvent, and membrane components in SARS-CoV-2 spike protein open and closed states. Employing s-long molecular dynamics simulations powered by high-performance cloud-computing and unsupervised density-driven adaptive sampling, we investigated the differences in bulk-solvent-glycan and protein-solvent-glycan interfaces between these states. We unraveled a sophisticated solvent-glycan polarization interaction network involving the N165/N343 residues that provide structural support for the open state and identified key water molecules that could potentially be targeted to destabilize this configuration. In the closed state, the reduced solvent polarization diminishes the overall N165/N343 dipoles, yet internal interactions and a reorganized sugar coat stabilize this state. Despite variations, our glycan-solvent accessibility analysis reveals the glycan shield capability to conserve constant interactions with the solvent, effectively camouflaging the virus from immune detection in both states. The presented insights advance our comprehension of viral pathogenesis at an atomic level, offering potential to combat COVID-19.

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↗

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↗

bioRxiv2022

????-actin plasticity is modulated by coordinated actions of histidine 73 methylation, nucleotide type, and ions

The functional importance of the methylation of histidine 73 (H73) in actin remains unclear. Focusing on cytoplasmic {beta}-actin, present in all mammalian cells, we use molecular dynamics simulations with a polarizable force field and adaptive sampling to examine the effects of H73 methylation. Our results show that methylation enhances nucleotide binding cleft opening, alters allosteric pathways connecting subdomains 2 and 4 (SD2 and SD4) in G-actin, and affects backdoor openings and inorganic phosphate release in F-actin, as validated by biochemical assays. These effects depend on the nucleotide and ions interacting with the actin. Together, our findings reveal how H73 methylation regulates {beta}-actin plasticity and integrates environmental cues.

biophysics↗