title: Molecular dynamics simulation and binding energy calculation for estimation of oligonucleotide duplex thermostability in RNA-based therapeutics.
abstract: For oligonucleotide-based therapeutics, a thorough understanding of the thermodynamic properties of duplex formation is critical to developing stable and potent drugs. For unmodified small interfering RNA (siRNA), DNA antisense oligonucleotide (AON) and locked nucleic acid (LNA), DNA/LNA modified oligonucleotides, nearest neighbor (NN) methods can be effectively used to quickly and accurately predict duplex thermodynamic properties such as melting point. Unfortunately, for chemically modified olignonucleotides, there has been no accurate prediction method available. Here we describe the potential of estimating melting temperature (T(m)) for nonstandard oligonucleotides by using the correlation of the experimental T(m) with the calculated duplex binding energy (BE) for oligonucleotides of a given length. This method has been automated into a standardized molecular dynamics (MD) protocol through Pipeline Pilot (PP) using the CHARMm component in Discovery Studio (DS). Results will be presented showing the correlation of the predicted data with experiment for both standard and chemically modified siRNA and AON.
authors.affiliation: Pfizer, Cambridge, Massachusetts 02139, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Shen
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Johnson
authors.forename: Susan
authors.initials: S
authors.lastname: Clugston
authors.forename: Hongwei
authors.initials: H
authors.lastname: Huang
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Butenhof
authors.forename: Robert V
authors.initials: RV
authors.lastname: Stanton
mesh_terms: D057205:Automation, Laboratory; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004247:DNA / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D004355:Drug Stability; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D009690:Nucleic Acid Conformation; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry / Q000235:genetics; D009841:Oligonucleotides / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry; D034741:RNA, Small Interfering / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D013053:Spectrophotometry; D013816:Thermodynamics; D044366:Transition Temperature
chemical_list: D009692:Nucleic Acid Heteroduplexes; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D004364:Pharmaceutical Preparations; D034741:RNA, Small Interfering; C477371:locked nucleic acid; D004247:DNA