Computational modeling of sequence-dependent DNA curvature using hydrodynamics

冈萨雷斯0706951 研究人员开发了一种计算方法，从短的，相对刚性的片段的流体动力学数据预测DNA的局部，序列依赖的曲率参数。 Themethod包括最小化的最小二乘功能whichquantified之间的差异理论和experimentalsedimentation速度为一个给定的收集碎片，其数值实现需要反复解决的外部斯托克斯型问题周围的各种细长，三维域。 研究工作集中在三个领域：（1）研究了刚性聚合物在Stokes型流体中的理论沉降速度，（2）基于核自适应Nystrom方法的新思想，设计和分析了计算理论沉降速度的快速、可证明收敛的边界元方法，（3）设计和分析了快速、可证明收敛的边界元方法，可靠的方法最小化aleast-squares沉降功能在空间ofsequencesependent曲率参数。DNA的序列依赖性曲率和柔性对于其包装到细胞中、被其他分子识别以及在生物化学重要过程中的构象变化至关重要。 然而，很少有实验方法可用于在碱基对水平上探测这些性质。本项目的目的是利用DNA在短长度尺度上的刚度，并开发一种方法，用于从短片段的流体动力学数据中估计局部的、序列依赖的曲率参数。 该方法是基于这样的观察，即不同形状的小的、相对坚硬的碎片在被迫通过粘性流体或通过稀释的凝胶时通常以不同的速度行进。 研究者试图发展一个足够精确的形状和速度之间的数学关系，并进一步使用这种关系来发展一种计算方法，从速度的测量来估计形状参数。这项研究的结果为量化DNA的内在序列依赖性曲率提供了新的工具，这反过来可能会增强对重要基因组区域以及DNA如何与其他分子相互作用的理解。

Gonzalez0706951 The investigator develops a computational method forestimating local, sequence-dependent curvature parameters for DNAfrom hydrodynamic data on short, relatively stiff fragments. Themethod consists of minimizing a least-squares functional whichquantifies the difference between theoretical and experimentalsedimentation speeds for a given collection of fragments, and itsnumerical implementation requires the repeated solution of anexterior Stokes-type problem around various slender,three-dimensional domains. The research effort is centered onthree areas: (1) the study of the theoretical sedimentation speedof a stiff polymer in a Stokes-type fluid with thermalfluctuations in different asymptotic limits, (2) the design andanalysis of fast, provably convergent boundary element methodsfor computing the theoretical sedimentation speed based on thenovel idea of a kernel-adapted Nystrom method, and (3) the designand analysis of fast, reliable methods for minimizing aleast-squares sedimentation functional over a space ofsequence-dependent curvature parameters. The sequence-dependent curvature and flexibility of DNA iscritical for its packaging into the cell, recognition by othermolecules, and conformational changes during biochemicallyimportant processes. However, few experimental methods areavailable for probing these properties at the basepair level. The objective of this project is to exploit the stiffness of DNAat short length scales and develop a method for estimating local,sequence-dependent curvature parameters from hydrodynamic data onshort fragments. The method is based on the observation thatsmall, relatively stiff fragments of different shape typicallytravel at different speeds when forced through a viscous fluid orthrough a dilute gel. The investigator seeks to develop asufficiently refined mathematical relation between shape andspeed and further use this relation to develop a computationalmethod to estimate shape parameters from measurements of speed. Results from this research lead to new tools for quantifying theintrinsic sequence-dependent curvature of DNA, which in turn maylead to an enhanced understanding of important genomic regionsand of how DNA interacts with other molecules.