Exploring RNA and protein three-dimensional structures by geometric algorithms .

摘要

Many problems in RNA and protein structures are related with their specific geometric properties. Geometric algorithms can be used to explore the possible solutions of these problems. This dissertation investigates the geometric properties of RNA and protein structures and explores three different ways that geometric algorithms can help to the study of the structures.;Determine accurate structures. Accurate details in RNA structures are important for understanding RNA function, but the backbone conformation is difficult to determine and most existing RNA structures show serious steric clashes (≥ 0.4 A overlap). I developed a program called RNABC (RNA Backbone Correction) that searches for alternative clash-free conformations with acceptable geometry. It rebuilds a suite (unit from sugar to sugar) by anchoring phosphorus and base positions, which are clearest in crystallographic electron density, and reconstructing other atoms using forward kinematics and conjugate gradient methods. Two tests show that RNABC improves backbone conformations for most problem suites in S-motifs and for many of the worst problem suites identified by members of the Richardson lab.;Display structure commonalities. Structure alignment commonly uses root mean squared distance (RMSD) to measure the structural similarity. I first extend RMSD to weighted RMSD (wRMSD) for multiple structures and show that using wRMSD with multiplicative weights implies the average is a consensus structure. Although I show that finding the optimal translations and rotations for minimizing wRMSD cannot be decoupled for multiple structures, I develop a near-linear iterative algorithm to converge to a local minimum of wRMSD. Finally I propose a heuristic algorithm to iteratively reassign weights to reduce the effect of outliers and find well-aligned positions that determine structurally conserved regions.;Distinguish local structural features. Identifying common motifs (fragments of structures common to a group of molecules) is one way to further our understanding of the structure and function of molecules. I apply a graph database mining technique to identify RNA tertiary motifs. I abstract RNA molecules as labeled graphs, use a frequent subgraph mining algorithm to derive tertiary motifs, and present an iterative structure alignment algorithm to classify tertiary motifs and generate consensus motifs. Tests on ribosomal and transfer RNA families show that this method can identify most known RNA tertiary motifs in these families and suggest candidates for novel tertiary motifs.