Structural Features of Specificity in Protein-DNA Recognition

University Of North Carolina Charlotte, Charlotte NC

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Abstract

DESCRIPTION (provided by applicant): Molecular interactions between proteins and DNA play crucial roles in many fundamental biological processes, such as DNA modification and gene regulation. DNA-binding proteins encompass various degrees of binding specificity, ranging from highly specific to non-specific. This proposal aims to investigate the dynamic structural features for achieving high degree of protein-DNA binding specificity. Current readout mechanisms are based on analysis of the snapshots of protein-DNA complex structures. Protein-DNA recognition, however, is a dynamic process involving structural fitting between proteins and DNA. More complete description is needed to fully understand specificity in protein-DNA recognition. With increasing number of high-resolution protein-DNA complex structures (holo) and their corresponding unbound protein structures (apo) in Protein Data Bank, we attempt to perform systematic studies to decipher the structural and dynamic code encrypting binding specificity between proteins and DNA using datasets with different degrees of binding specificity. Specifically, we will implement two individual yet highly complementary approaches: (1) a comparative analysis of holo-apo pairs that cover the specificity landscape to investigate the dynamic features that contribute to specific protein-DNA interaction during the recognition process; and (2) an integrative method by combining sequence analysis, homology modeling and comparative molecular dynamics (MD) simulations to study the role of flexibility in binding specificity of homeodomains.