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A. JOSHUA WAND, Ph.D.

Benjamin Rush Professor of Biochemistry and Biophysics

905 Stellar-Chance Laboratories
Department of Biochemistry & Biophysics
University of Pennsylvania
Philadelphia, PA 19104
215-573-7288 (office)
215-573-7289 (main lab)
215-573-5969 (NMR lab)
215-573-7290 (fax)
wand@mail.med.upenn.edu

Ph.D. University of Pennsylvania (1984)

pubmed

DESCRIPTION OF RESEARCH INTERESTS:

Dr. Wand's research focuses on exploring the relationships between static structure, structural dynamics and function in a range of protein systems. A key concept is the balance between changes in structure (enthalpy) and dynamics (entropy) in the setting of the free energy of association between proteins. They are also interested in similar issues in the context of interactions with small ligands such as drugs. Historically, the connection between motion and entropy has been difficult to make experimentally. Over the past few years, they have been developing a dynamical proxy for entropy or an “entropy meter” and have done so through an empirical calibration. The resulting quantitative interpretation of motion measured by NMR relaxation methods has revealed a broad and rather remarkable role for protein conformational entropy in protein function. Through these studies a remarkably rich manifold of fast dynamical modes have also been revealed and a surprising functional role for them discovered. Initially focusing on calmodulin as a model demonstration system, the Wand lab is now investigating a range of proteins involved in a wide variety of functions that may be energetically influenced by conformational entropy. These include the lac repressor system, lysozyme, the oncogenic Ras protein GTPases among several others.

Another major effort in the Wand lab is also committed to continuing improvement and development of novel NMR techniques. They have recently focused on high pressure NMR to probe the protein ensemble, sparse sampling methods for rapid and sensitivity-optimized data collection, NMR relaxation methods to measure conformational dynamics throughout the protein and a novel method to approach large soluble, unstable and membrane proteins by solution NMR methods. The latter approach involves the use of reverse micelle encapsulation to provide a protective environment for proteins to allow them to be dissolved in low viscosity fluids such as liquid ethane. The initial idea was to use the low viscosity of ethane to overcome the slow tumbling problem for solution NMR spectroscopy presented by large protein in water. Applications have since been expanded to studies of proteins of marginal stability by employing the confined space of the reverse micelle, suppression of protein aggregation to allow study of intermediates of aggregation such as occur in amyloid formation, and studies of both integral and peripherally anchored membrane proteins. Most recently, they have employed some special properties of reverse micelle to overcome barriers to characterizing the dynamical character of the protein hydration layer and its influence on protein dynamics. The hydration shell of proteins is found to be remarkably heterogeneously dynamic with a clustering of dynamical character apparent. Even more exciting is an apparent correlation of the clustering of the motional character of hydration water with functional surfaces of the protein. Related to this is the coupling of the motion of hydration water with the motions of the protein.

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