title: Focus on PNA Flexibility and RNA Binding using Molecular Dynamics and Metadynamics.
abstract: Peptide Nucleic Acids (PNAs) can efficiently target DNA or RNA acting as chemical tools for gene regulation. Their backbone modification and functionalization is often used to increase the affinity for a particular sequence improving selectivity. The understanding of the trading forces that lead the single strand PNA to bind the DNA or RNA sequence is preparatory for any further rational design, but a clear and unique description of this process is still not complete. In this paper we report further insights into this subject, by a computational investigation aiming at the characterization of the conformations of a single strand PNA and how these can be correlated to its capability in binding DNA/RNA. Employing Metadynamics we were able to better define conformational pre-organizations of the single strand PNA and γ-modified PNA otherwise unrevealed through classical molecular dynamics. Our simulations driven on backbone modified PNAs lead to the conclusion that this γ-functionalization affects the single strand preorganization and targeting properties to the DNA/RNA, in agreement with circular dichroism (CD) spectra obtained for this class of compounds. MD simulations on PNA:RNA dissociation and association mechanisms allowed to reveal the critical role of central bases and preorganization in the binding process.
authors.affiliation: Dipartimento di Chimica, University of Parma, Italy, 43124, Italy.
authors.forename: Massimiliano Donato
authors.initials: MD
authors.lastname: Verona
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, c/o Università della Svizzera Italiana Campus, 6900 Lugano, Switzerland.|Facoltà di Informatica, Instituto di Scienze Computazionali, Università della Svizzera Italiana, 6900 Lugano, Switzerland.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Verdolino
authors.affiliation: Department of Chemistry and Applied Biosciences, ETH Zurich, c/o Università della Svizzera Italiana Campus, 6900 Lugano, Switzerland.|Facoltà di Informatica, Instituto di Scienze Computazionali, Università della Svizzera Italiana, 6900 Lugano, Switzerland.
authors.forename: Ferruccio
authors.initials: F
authors.lastname: Palazzesi
authors.affiliation: Dipartimento di Chimica, University of Parma, Italy, 43124, Italy.|National Institute for Biostructures and Biosystems (INBB)-Viale delle Medaglie d'Oro, 305, 00136 Roma, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Corradini
mesh_terms: D001665:Binding Sites; D002942:Circular Dichroism; D019295:Computational Biology / Q000379:methods; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009690:Nucleic Acid Conformation; D020135:Peptide Nucleic Acids / Q000737:chemistry* / Q000378:metabolism*; D012313:RNA / Q000378:metabolism*
chemical_list: D020135:Peptide Nucleic Acids; D012313:RNA