The 2014 Lectures in Chemistry and Biology: Molecular Conformational Fluctuations: Origins of Biological Specificity and Applications in Pharmacochemistry
Francis Crick once said: "When you do not understand function, study structure". The crystallographers, followed this advice and gave us a large repertoire of protein and nucleic acid structures. In some cases, this linkage was obvious but not for all.
When Kurt Wutrhich introduced Nuclear Magnetic Resonance spectroscopy (NMR) to the study of proteins a whole new appreciation of the structure/function linkage became apparent. The reason is easily understood: Crystallography captures the structure of the molecular conformation which yields the best crystal lattice and where the molecules have extremely low mobility and flexibility; essentially behaving as rigid bodies. In contrast, NMR reveals how macromolecules behave in solution; it captures molecular dynamics. And certain conformational states within the range of this dynamic ensemble are coupled to specific functions.
The regulation of all cellular activities is achieved through the action of specialized molecules, mostly proteins (and some RNAs). Both of these are, in physical and chemical terms, large multiatomic ensembles bonded together in some specific sequence of subunits (amino acids or nucleotides). The functional properties of each of these ensembles are manifested only when each of them folds into a unique 3-D structure (fold), sometimes with several thermodynamic sub-domains. Recent evidence is telling us that even this 3-D structure is an average among a multitude of conformational states, all in rapid and reversible equilibrium. Sometimes, the population of these sub-states is driven to a completely different fold. Macromolecules in solution "dance" and these dances are influenced by the properties of their microscopic environment, i.e., the composition of the solvent in which they "swim", just as Chris Anfinsen had predicted many years earlier: the essential linkage between amino acid sequence and environment to yield a unique functional structure.
This year our Lecture Series will focus on the basic methodologies for capturing the conformational fluctuations of macromolecules as they relate to protein stability, folding and function. Furthermore, we will examine the thermodynamics of these fluctuations and the selectivity and specificity of interactions between macromolecules and with the ligands that affect them. The latter will be linked to specific examples of cellular regulation (allostery, transcription, translation, transport, etc) and with the design and optimization of novel pharmaceuticals (intelligent drug design) that can modulate these conformational fluctuations. It is the hope that at the end, the students would be able to better appreciate that molecular selectivity and specificity are emerging properties of the system and their emergence can be manipulated and controlled to achieve tangible benefits.
Professor, ETH, Zurich, Switzerland and
The Scripps Research Institute, La Jolla, CA, USA.
Nobel Prize (2002) in Chemistry
Professor, Department of Biology, Johns Hopkins University, Baltimore, USA
Professor and Chair, Department of Biology, Johns Hopkins University, Baltimore, USA
Birthe B. Kragelund
Professor, Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Professor, Leibniz Institut fur Moleculare Pharmakologie, Berlin, Germany.
Hans W. Spiess
Professor, Max Planck Institute for Polymer Research, Mainz, Germany
Professor, Harvard Medical School, Boston, USA