Research Overview

The long-term objective of our research is to elucidate the molecular recognition mechanisms used by proteins to control biomineralization processes. A variety of interesting proteins that are found in mineralized tissues act as nature's crystal engineers, where they control the growth of inorganic composites such as hydroxyapatite (HAP) (the mineral phase found in bone/teeth). A particularly important class of acidic proteins found in hard tissues is known to regulate normal hard tissue formation and remodeling, and they are also involved in pathological processes such as dental caries, kidney stone formation and arterial calcification. However, due to the difficulties in studying the protein structure and function at inorganic solid surfaces, there is still remarkably little known of the molecular structure-function relationships governing hard tissue engineering.  Our group has been developing and applying solid-state NMR (ssNMR) techniques to determine protein structure and dynamics on their biologically relevant hydroxyapatite surface. These studies have led us to the beginnings of a high-resolution model for the acidic salivary protein statherin. Statherin N-terminal Interaction
with  HAP Our goal for the next few years is to test and develop using NMR and molecular modeling a full three-dimensional statherin structure that connects the molecular mechanisms underlying hydroxyapatite adsorption thermodynamics and crystal engineering function. This research involves collaborations with the groups of David Castner in Chemical Engineering, Patrick Stayton in Bioengineering, and Charles Campbell in Chemistry.

Another long-standing research interest is the study of the role played by dynamics in protein-nucleic acid recognition. Our objective is to probe nucleic acid dynamics through the conjoint use of solution and solid-state deuterium NMR. By exploiting the synergy between the two methods, we have measured internal motions quantitatively enough and with sufficient coverage of motional time scales to begin to correlate motions with function. Problems of current interest include how motion affects recognition of a DNA dodecamer containing the recognition site for the Hha I methyltransferase, the interaction between HIV TAR and Tat peptide constructs, and how motion affects recognition in human U1A protein, a paradigm for highly specific RNA-protein interactions. This research involves collaborations with the group of Gabriele Varani in Biochemistry.