用改进的初级阶跃模拟重温杂交动力学

IF 4.7 2区 生物学 Q1 GENETICS & HEREDITY Mobile DNA Pub Date : 2023-01-01 DOI:10.4230/LIPIcs.DNA.29.5
Jordan Lovrod, Boyan Beronov, Chenwei Zhang, Erik Winfree, Anne Condon
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引用次数: 1

摘要

核酸链通过形成和破坏沃森-克里克碱基对来进行反应,可以设计成复杂的纳米级结构或设备。控制这样的系统需要准确预测反应速率和相互作用链的折叠路径。Multistrand等模拟器使用连续时间马尔可夫链(ctmc)来模拟这些动力学性质,ctmc的状态和转变分别对应于二级结构和基本碱基对的变化。CTMC的瞬态动力学是由一个动力学模型决定的,该模型将跃迁速率分配给状态对,反应速率可以用其CTMC的平均首次通过时间(MFPT)来估计。然而,Multistrand的使用受到其运行速度慢的限制,特别是在罕见事件中,并且其速率预测的质量受到校准不良和过于简单的动力学模型的影响。前一种限制可以通过构建截断的ctmc来解决,这些ctmc只包括一小部分状态和转换,可以手动选择或通过模拟选择。作为解决后一个限制的第一步,在早期的工作中,使用一个小型的DNA反应速率实验数据集和一组固定的人工截断的ctmc(我们称之为假设路径(AP)状态空间),对arrhenius型动力学模型进行了贝叶斯后验推理。在这项工作中,我们扩展了这一方法,引入了一个新的先验模型,该模型直接由参数的物理意义驱动,与基本速率的实验测量相兼容,并使用了1105个反应的更大数据集以及从最近引入的随机路径细化(PE)方法获得的更大截断状态空间。我们通过动力学参数评估后验分布的质量,以及使用AP和PE状态空间预测后验反应速率的质量。最后,我们使用新的参数化PE状态空间和多链模拟来研究Hata等人的数据集中螺旋杂交反应速率的强烈变化。虽然我们发现了杂化成核-压缩模型的有力证据,在经典意义上,限速相由达到临界稳定性的小“核”的基本步骤组成,但直到成核的轨迹集合的强烈序列依赖结构似乎比Hata等人在模型中假设的要丰富得多。特别是,第一次结合和成核之间的轨迹段不是由成核位点的碰撞概率所主导,而是倾向于访问许多涉及错核和发夹的二级结构,并且对克服成核屏障的概率有相当大的影响。
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Revisiting Hybridization Kinetics with Improved Elementary Step Simulation
Nucleic acid strands, which react by forming and breaking Watson-Crick base pairs, can be designed to form complex nanoscale structures or devices. Controlling such systems requires accurate predictions of the reaction rate and of the folding pathways of interacting strands. Simulators such as Multistrand model these kinetic properties using continuous-time Markov chains (CTMCs), whose states and transitions correspond to secondary structures and elementary base pair changes, respectively. The transient dynamics of a CTMC are determined by a kinetic model, which assigns transition rates to pairs of states, and the rate of a reaction can be estimated using the mean first passage time (MFPT) of its CTMC. However, use of Multistrand is limited by its slow runtime, particularly on rare events, and the quality of its rate predictions is compromised by a poorly-calibrated and simplistic kinetic model. The former limitation can be addressed by constructing truncated CTMCs, which only include a small subset of states and transitions, selected either manually or through simulation. As a first step to address the latter limitation, Bayesian posterior inference in an Arrhenius-type kinetic model was performed in earlier work, using a small experimental dataset of DNA reaction rates and a fixed set of manually truncated CTMCs, which we refer to as Assumed Pathway (AP) state spaces. In this work we extend this approach, by introducing a new prior model that is directly motivated by the physical meaning of the parameters and that is compatible with experimental measurements of elementary rates, and by using a larger dataset of 1105 reactions as well as larger truncated state spaces obtained from the recently introduced stochastic Pathway Elaboration (PE) method. We assess the quality of the resulting posterior distribution over kinetic parameters, as well as the quality of the posterior reaction rates predicted using AP and PE state spaces. Finally, we use the newly parameterised PE state spaces and Multistrand simulations to investigate the strong variation of helix hybridization reaction rates in a dataset of Hata et al. While we find strong evidence for the nucleation-zippering model of hybridization, in the classical sense that the rate-limiting phase is composed of elementary steps reaching a small “nucleus” of critical stability, the strongly sequence-dependent structure of the trajectory ensemble up to nucleation appears to be much richer than assumed in the model by Hata et al. In particular, rather than being dominated by the collision probability of nucleation sites, the trajectory segment between first binding and nucleation tends to visit numerous secondary structures involving misnucleation and hairpins, and has a sizeable effect on the probability of overcoming the nucleation barrier.
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来源期刊
Mobile DNA
Mobile DNA GENETICS & HEREDITY-
CiteScore
8.20
自引率
6.10%
发文量
26
审稿时长
11 weeks
期刊介绍: Mobile DNA is an online, peer-reviewed, open access journal that publishes articles providing novel insights into DNA rearrangements in all organisms, ranging from transposition and other types of recombination mechanisms to patterns and processes of mobile element and host genome evolution. In addition, the journal will consider articles on the utility of mobile genetic elements in biotechnological methods and protocols.
期刊最新文献
International congress on transposable elements (ICTE 2024) in Saint Malo: breaking down transposon waves and their impact. Accelerating de novo SINE annotation in plant and animal genomes. Association of hyperactivated transposon expression with exacerbated immune activation in systemic lupus erythematosus. Widespread HCD-tRNA derived SINEs in bivalves rely on multiple LINE partners and accumulate in genic regions. Correction: Transposon-derived introns as an element shaping the structure of eukaryotic genomes.
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