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The overall goal of this collaborative project is to develop methods for analyzing protein-nucleic acid interactions. Nucleic acid-binding proteins have a central role in all aspects of genetic activity within an organism, such as transcription, replication, and repair. Thus, it is extremely important to examine the nature of complexes that are formed between proteins and nucleic acids, as they form the basis of our understanding of how these processes take place. Over the past decade, the world has witnessed a great expansion in the determination of high-quality structures of nucleic acid-binding proteins. As a result, the number of such structures has seen a constant increase in the Protein Data Bank (PDB) (1) and the Nucleic Acid Database (NDB) (2). These structures, especially those of proteins in complex with DNA, have provided valuable insight into the stereochemical principles of binding, including how particular base sequences are recognized and how the nucleic acid structure is quite often modified on binding. In this project, we designed several approaches to characterize and classify the properties of both protein-DNA and protein-RNA complexes. In work done in the previous grant period, we developed methods to use experimental data to evaluate nucleic acid crystal structures in order to ensure that the structures utilized in future studies would be of high quality. The methodology was collated in the standalone software package SFCHECK (3) [A], and an applied survey of structures in the NDB produced very positive results. With this quality control mechanism in place, we then analyzed DNA-binding sites on proteins by studying the distortions observed in DNA structures bound to protein. From our observations, we found that DNA-binding proteins present a very different binding surface to those that bind other proteins and defined three modes of protein binding [B]. Following this survey, we classified DNA-binding proteins into eight different structural/functional groups [C]. This classification highlighted the diversity of protein-DNA complex geometries found in nature and emphasized the importance of interactions between alpha helices and the major groove--the main bind partner with DNA in roughly half of the protein families under study. These studies gave us the insight to seed our future work in the current project described here, as we observed the repeated presence of the helix-turn-helix (HTH) and zinc-coordinating motifs, and how they present an alpha helix on the surfaces of structurally diverse proteins ready for interaction with DNA [D, E, F, G, H]. Structure-based methods for predicting DNA-binding included scanning of 3D structural templates, use of the electrostatic potential to select generic DNA-binding residue patches, and a statistical model based on geometrical measures such as the recognition helix/second helix hydrophobic interaction area of the HTH motif. A recent study worked to incorporate structural data into a sequence-based method of motif detection. Another, more general, study at Rutgers developed a classification model to annotate DNA-binding proteins based on their three-dimensional (3D) structural features. As a necessary step to further understanding protein RNA interactions [I] we developed new visualization tools and methods to classify RNA conformation [J,K]. The tools developed are available for use by the scientific community through the NDB

PROTEIN NUCLEIC ACID INTERACTIONS GRANT # DE-FG02-96ER62166 FINAL REPORT