Biomolecular dynamics, structure, and function; NMR spectroscopy
Arthur Palmer uses NMR spectroscopy to elucidate the coupling between conformational dynamical properties and biological functions of proteins. His research extends from development of novel methods in NMR spectroscopy, computational and theoretical analyses of protein dynamics, and applications to protein folding, molecular recognition, and catalysis.
Palmer has a longstanding interest in the temperature dependence of stability and activity of proteins. His laboratory performed the first global characterization of the temperature dependence of intramolecular motions in an enzyme, specifically E. coli ribonuclease H. Changes in conformational fluctuations with increasing temperature identified the proposed earliest event in thermal denaturation. More recently, this work has expanded to include comparisons between the homologous enzyme from Thermus thermophilus, indicating that an inserted glycine residue, conserved in most thermophiles, is responsible for the differences in conformational dynamical behavior between the mesophilic and thermophilic ribonucleases H.
Palmer pioneered the use of statistical mechanical methods to interpret NMR spin relaxation studies of proteins. Expressions were derived for the contributions to the changes in free energy arising from conformational fluctuations of individual sites in proteins. Applications of this approach demonstrated that calcium ligation by calbindin D9k and DNA binding by GCN4 involved a significant entropic penalty due to rigidification of the binding sites. Recently, molecular dynamics simulations have been used to obtain novel insights into the mechanisms of conformational dynamics of proteins, as well as to benchmark modern simulation protocols.
Investigation of dynamic properties of proteins on biologically important microsecond-millisecond time scales has been revitalized by the development, in the Palmer laboratory, of new approaches for the measurement and interpretation of chemical exchange phenomena, including relaxation compensated and TROSY Hahn echo, Carr-Purcell-Meiboom-Gill, and R1r experiments. Most recently, these efforts have been extended for residual dipolar couplings, opening a new avenue for characterizing protein dynamic and kinetic properties. These methods have been employed to determine the mechanism of strand swapping in cadherins, the recognition of ADP by ABC transporters, and the kinetics of folding of proteins at equilibrium in solution.
Palmer co-authored of the textbook Protein NMR Spectroscopy: Principles and Practice (Academic Press, 1996 and 2007), now the standard text for the study of biological NMR spectroscopy at the graduate and postdoctoral level. His laboratory also freely provides software for analyzing NMR spin relaxation data, including the widely used “modelfree” program.
- V. Z. Miloushev, F. Bahna, C. Ciatto, B. Honig, L. Shapiro, and A. G. Palmer, Dynamic properties of a type II cadherin adhesive domain: Implications for the mechanism of strand-swapping of classical cadherins, Structure 16, 1195-1205 (2008).
- N. Trbovic, B. Kim, R. A. Friesner, and A. G. Palmer, Structural analysis of protein dynamics by MD simulations and NMR spin relaxation, Proteins 71, 684-694 (2008).
- T. I. Igumenova, U. Brath, M. Akke, and A. G. Palmer, Characterization of chemical exchange using residual dipolar coupling, J. Am. Chem. Soc. 129, 13396-13397 (2007).
- J. Butterwick and A. G. Palmer, An inserted Gly residue fine tunes dynamics between mesophilic and thermophilic ribonucleases H, Protein Sci. 15, 2697-2707 (2006).
- M. J. Grey, Y. Tang, E. Alexov, C. J. McKnight, D. P. Raleigh, and A. G. Palmer, Characterizing a partially folded intermediate of the villin headpiece domain under non-denaturing conditions: Contribution of His41 to the pH-dependent stability of the N-terminal subdomain, J. Mol. Biol. 355, 1078-1094 (2006).