Biology subjects

D'Anna, L.

Publications and source records attributed to D'Anna, L..

3 recordsLinked to original sources

bioRxiv2023

Mechanism of the Covalent Inhibition of Human Transmembrane Protease Serine 2 as an Original Antiviral Strategy

The Transmembrane Protease Serine 2 (TMPRSS2) is a human enzyme which is involved in the maturation and post-translation of different proteins. In addition of being overexpressed in cancer cells, TMPRSS2 plays a further fundamental role in favoring viral infections by allowing the fusion of the virus envelope and the cellular membrane, notably in SARS-CoV-2. In this contribution we resort to multiscale molecular modeling to unravel the structural and dynamical features of TMPRSS2 and its interaction with a model lipid bilayer. Furthermore, we shed light into the mechanism of action of a potential inhibitor (Nafamostat), determining the free-energy profile associated with the inhibition reaction, and showing the facile poisoning of the enzyme. Our study, while providing the first atomistically resolved mechanism of TMPRSS2 inhibition, is also fundamental in furnishing a solid framework for further rational design targeting transmembrane proteases in a host-directed antiviral strategy. TOC GRAPHICS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/537985v1_ufig1.gif" ALT="Figure 1"> View larger version (108K): org.highwire.dtl.DTLVardef@19dd8c9org.highwire.dtl.DTLVardef@394c0org.highwire.dtl.DTLVardef@11ad383org.highwire.dtl.DTLVardef@347a8c_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Resolving a Guanine-Quadruplex Structure in the SARS-CoV-2 Genome through Circular Dichroism and Multiscale Molecular Modeling.

The genome of SARS-CoV-2 coronavirus is made up of a single-stranded RNA fragment that can assume a specific secondary structure, whose stability can influence the virus ability to reproduce. Recent studies have identified putative guanine quadruplex sequences in SARS-CoV-2 genome fragments that are involved in coding for both structural and non-structural proteins. In this contribution, we focus on a specific G-rich sequence referred as RG-2, which codes for the non-structural protein 10 (Nsp10) and assumes a guanine-quadruplex (G4) arrangement. We provide the secondary structure of the RG-2 G4 at atomistic resolution by molecular modeling and simulation, validated by the superposition of experimental and calculated electronic circular dichroism spectrum. Through both experimental and simulation approaches, we have demonstrated that pyridostatin (PDS), a widely recognized G4 binder, can bind to and stabilize RG-2 G4 more strongly than RG-1, another G4 forming sequence that was previously proposed as a potential target for antiviral drug candidates. Overall, this study highlights RG-2 as a valuable target to inhibit the translation and replication of SARS-CoV-2 paving the way towards original therapeutic approaches against emerging RNA viruses.

biophysics↗

bioRxiv2023

Predicting the Three-dimensional Structure of the c-KIT Oncogene Promoter and the Dynamics of Strongly Coupled Guanine-Quadruplexes

Guanine-quadruplexes (G4s) are non-canonical DNA structures that play important protective and regulatory roles within cells, influencing, for instance, gene expression. Although the secondary structure of many human G4s is well characterized, in several gene-promoter regions multiple G4s are located in close proximity and may form three-dimensional structures which could ultimately influence their biological roles. In this contribution, we analyze the interplay between the three neighboring G4s present in the c-KIT proto-oncogene promoter, namely WK1, WSP and WK2. In particular, we highlight how these three G4s are structurally linked and how their crosstalk favors the formation of a parallel structure for WSP, differently from what observed for this isolated G4 in solution. Relying on all-atom molecular dynamic simulations exceeding the s time-scale and using enhanced sampling methods, we provide the first computationally-resolved structure of a well-organized G4 cluster in the promoter of a crucial gene involved in cancer development. Our results indicate that neighboring G4s influence their mutual three-dimensional arrangement and provide a powerful tool to predict and interpret complex DNA structures that ultimately can be used as starting point for drug discovery purposes.

biophysics↗