Molecular Dynamics Simulation and Binding Energy Calculation for Estimation of Oligonucleotide Duplex Thermostability in RNA-Based Therapeutics
Molecular Dynamics Simulation and Binding Energy Calculation for Estimation of Oligonucleotide Duplex Thermostability in RNA-Based Therapeutics
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DOI：
10.1021/ci200141j
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发表时间：
2011-08-01
影响因子：
5.6
通讯作者：
Stanton, Robert V.
中科院分区：
文献类型：
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作者：
Shen, Lingling;Johnson, Theresa L.;Stanton, Robert V.
对于基于寡核苷酸的治疗，深入了解双链形成的热力学性质对于开发稳定和有效的药物至关重要。对于未修饰的小干扰RNA （siRNA）、DNA反义寡核苷酸（AON）和锁定核酸（LNA）、DNA/LNA修饰的寡核苷酸，最近邻（NN）方法可以有效地快速准确地预测熔点等双热力学性质。不幸的是，对于化学修饰的寡核苷酸，目前还没有准确的预测方法。在这里，我们描述了利用实验Tm与给定长度寡核苷酸计算的双键结合能（BE）的相关性来估计非标准寡核苷酸熔化温度（T-m）的潜力。使用Discovery Studio （DS）中的CHARMm组件，通过Pipeline Pilot （PP）将该方法自动化为标准化的分子动力学（MD）协议。结果将显示标准siRNA和化学修饰siRNA和AON的预测数据与实验的相关性。
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 Tm 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.