This action funds an NSF Postdoctoral Research Fellowship for FY 2010. The fellowship supports a research and training plan entitled "Experimental and Computational Investigation of the Role of Protein Conformational Dynamics in Enzymatic Activity" for Paul Robustelli. The host institution for this research is Columbia University, and the sponsoring scientist is Author G. Palmer III.
The biological functions of proteins are dictated by both their structures and their conformational dynamics. In many cases characterizing the conformational dynamics of a protein has been shown to be essential in understanding how it carries out its biological function and how it interacts with other molecules, and has provided valuable insights into molecular mechanisms of catalysis, recognition, signaling, and the binding of drugs to pharmaceutical targets. In this project, new computational techniques are developed to characterize how differences in conformational dynamics dictate the variable enzymatic activities in a family of structurally similar Ribonuclease enzymes involved in DNA replication, repair, and transcription. These techniques combine the interpretation of experimental measurements, made with nuclear magnetic resonance, with molecular dynamics computer simulations to elucidate, and thermodynamically characterize, the conformational dynamics of proteins at atomic resolution.
This investigation determines the role of protein dynamics in mechanisms of enzymatic catalysis for a biologically important class of enzymes and creates new freely distributed computational tools that can be used to understand the link between protein dynamics and function in numerous biological processes. Training goals include learning experimental protein structure and dynamics measurements using nuclear magnetic resonance and developing computational skills in novel protein structure calculation techniques and molecular dynamics simulations. This research is integrated with the mentoring of research students and results are incorporated into special topics lectures in courses on molecular biophysics and nuclear magnetic resonance of macromolecules at Columbia University.
Proteins, which are large biological molecules consisting of chains of amino acids, perform a large array of functions in living organisms. They are responsible for activities such as replicating DNA, catalyzing metabolic reactions, and sensing and responding to environmental stimuli. Many diseases have been shown to be associated with the malfunction of specific proteins, and proteins currently represent the majority of pharmaceutical drug targets. It has long been recognized that the biological functions and the interactions of proteins with other molecules can be dictated by their three dimensional structures, or how the atoms of the molecule are arranged in space. In recent years, it has become increasingly clear that the functions and interactions of proteins cannot be entirely explained by their structure, and are also dependent on their conformational dynamics, or how the positions of the atoms in the molecule fluctuate in time. In many cases characterizing the conformational dynamics of a protein has been shown to be essential in understanding how it carries out its biological function and how it interacts with other molecules, and has provided valuable insights into molecular mechanisms of catalysis, recognition, signaling, and the binding of drugs to pharmaceutical targets. In this investigation, new computational techniques were developed to study the conformational dynamics of proteins, and these techniques have been applied to characterize how differences in conformational dynamics can explain the variable enzymatic activity of a family of structurally similar enzymes involved in DNA replication, repair, and transcription. These techniques combine the interpretation of experimental measurements with computer simulations to elucidate the conformational dynamics of proteins at atomic resolution. This investigation has elucidated the role of protein conformational dynamics in enzymatic catalysis for a biologically important class of enzymes and introduced a new method that can be used to understand the link between protein dynamics and protein function in numerous biological processes.
