Interdisciplinary research – Direct Imaging of Single Molecule

Interdisciplinary research has immense potential. I have talked about one of the major discoveries of modern science based on interdisciplinary research in my previous blog, posted on 29th July 2013 (http://blog.manuscriptedit.com/2013/07/ interdisciplinary-research-nobel-prize-chemistry-won-biologists/). Today, let us take another example, where one chemist and one physicist came together and presented us with the direct image of internal covalent bond structure of a single molecule using one of the advanced imaging tools, non-contact Atomic force microscope (nc-AFM). Image1Dr. Felix R.Fischer (http://www.cchem.berkeley.edu/frfgrp/), a young Assistant Professor of Chemistry at University of California (UC), Berkeley along with his collaborator Dr. Michael Crommie (http://www.physics.berkeley.edu/research/crommie/home), also a UC Berkeley Professor of Physics captured the images of internal bond structure of oligo (phenylene-1, 2 ethynylenes) [Reactant1] when it undergoes cyclization to give different cyclic compounds (one of which is shown in the inset picture http://newscenter.berkeley.edu/2013/05/30/scientists-capture-first-images-of-molecules-before-and-after-reaction/). Chemists generally determine structure of molecules using different spectroscopic techniques (NMR, IR, Uv-vis, etc.) in an indirect manner. The molecular structures, we generally see in the textbooks result from the indirect way of structure determination, either theoretical or experimental or both. It is more like putting together various parts to solve a puzzle. But now, with this ground breaking work of two scientists from UC Berkeley, one can directly see for the very first time in the history of science, how a single molecule undergoes transformation in a chemical reaction, how the atoms reorganized themselves at a certain condition to produce another molecule. No more solving puzzle for next generation of chemists to determine the molecular structure.

HOW interdisciplinary research made it possible:

Well, it was not easy task for the scientists to come up with these spectacular molecular images. Imaging techniques such as scanning tunneling microscopy (STM), tunneling electron microscopy (TEM), have their limitations, and are often destructive to the organic molecular structure. Advanced technique like nc-AFM where a single carbon monoxide molecule sits on the tip (probe) helps in enhancing the spatial resolution of the microscope, and this method is also non-destructive. The thermal cyclization of the Reactant 1 was probed on an atomically cleaned silver surface, Ag(001) under ultra-high vacuum at single molecular level by STM and nc-AFM. Before probing, the reaction surface and the molecules were chilled at liquid helium temperature, 40K (-2700C). Then the researchers first located the surface molecules by STM and then performed further finetuning with nc-AFM, and the result is what we see in the inset picture. For cyclization, the Reactant 1 was heated at 900C, the products were chilled and probed.  Chilling after heating did not alter the structure of the products. The mechanism of thermal cyclization was also clearly understood, and the mechanistic pathway was in agreement with the theoretical calculations. From the blurred images of STM, Dr. Fischer and Dr. Crommie along with their coworkers presented us crystal clear molecular images with visible internal bond structure. This ground breaking work shows the potential of nc-AFM and unveils secrets of surface bound chemical reactions which will definitely have a huge impact on oil and chemical industries where heterogeneous catalysis is widely used. This technique will also help in creating customized nanostructure for use in electronic devices.

Again this path breaking work was possible due to the collaborative research between chemists and physicists. Hence, the interdisciplinary researches have endless potential.

References

1.    de Oteyza DG, Gorman P, Chen Y-C, Wickenburg S, Riss A, Mowbray DJ, Etkin G, Pedramrazi Z, Tsai H-Z, Rubio A, Crommie MF, Fischer FR. Direct Imaging of Covalent bond structure in Single-molecule chemical reactions. Science (2013); 340: 1434-1437

 

Interdisciplinary research – Nobel Prize for Chemistry was awarded to two Biologists

Modern scientific research does not confine itself to any restricted boundary.  Nowadays, it is all about interdisciplinary research. In 2012, Nobel Prize for Chemistry (http://www.nobelprize.org/nobel_prizes/chemistry/)was awarded to two eminent biologists, Prof. Robert J Lefkowitz and Prof. Brian Kobika, for their crucial contribution in unveiling the signalling mechanism of G protein-coupled receptors (GPCRs). It’s a lifetime work of both the scientists. Dr. Lefkowitz, an investigator at Howard Hughes Medical Institute (HHMI) at Duke University, is also James B Duke Professor of Medicine and of Biochemistry at Duke University Medical Center, Durham, NC, USA. Dr. Kobika, earlier a postdoctoral fellow in Dr. Lefkowitz’s laboratory, is currently Professor of Molecular and Cellular Physiology at Stanford University, School of Medicine, Stanford, CA, USA.

Transmembrane signalling of one GPCR “caught in action” by X-ray crystallography

GTP (guanosine triphosphate) binding proteins (G-protein) act as molecular switches in transmitting signals from different stimuli outside the cell to inside the cell. However, for doing this G-protein needs to be activated, and that is where GPCRs play the most important role. They sit in the cell membranes throughout the body. GPCRs, also known as seven transmembrane (pass through the cell membrane seven times) domain proteins, detect the external signals like odor, light, flavor as well as the signals within the body such as hormones, neurotransmitter.1 Once the GPCRs detect a signal, the signal is transduced in certain pathway and finally activate the G-protein. In response, the activated G-protein triggers different cellular processes. Binding of a signalling molecule or ligand to the GPCR causes conformational changes in the GPCR structure. As a result of extensive research of 20 long years, Dr. Lefkowitz and Dr. Kobika not only identified 800 members of GPCRs family in human but also caught in action how these receptor proteins actually carry out the signal transduction with the help of high resolution X-ray crystallography. The crystal structure of ß2-adrenergic receptor (ß2AR), a member of the human GPCRs family was reported by Dr. Kobika and his colleagues in 2007.2 The hormones adrenaline and noradrenaline are known to activate ß2AR, and the activated ß2AR triggers different biochemical processes which help in speeding up the heart and opening airways as body’s fight response. The ß2AR is a key ingredient in anti-asthma drugs. One of the major breakthroughs came in 2011 when Dr. Kobika and his co-workers unveiled for the first time the exact moment of the transmembrane signalling by a GPCR. They reported the crystal structure of “the active state ternary complex composed of agonist-occupied monomeric ß2AR and nucleotide-free Gs heterotrimer”.3 A major conformational change in ß2AR during signal transduction was discovered.

Now what is so special about GPCRs? Well, these proteins belong to one of the largest families of  all human proteins. GPCRs are involved in most of the physiological activities, and hence are  the targets of a number of drugs. Determination of the molecular structures of this class of receptors not only helps the researchers to understand the actual mechanism of different cellular processes but also help them to design life saving and more effective drugs. So, in a nut shell, this scientific breakthrough was possible due to the involvement of experts of different areas of science such as, chemistry, biochemistry, molecular and cellular biology, structural biology, cardiology, crystallography.

 

References

 

  1. Lefkowitz, R. J. Seven transmembrane receptors: something old, something new. Acta Physiol. (Oxf.) 190, 9–19 (2007).
  2. Rasmussen, S. G. et al. Crystal structure of the human b2 adrenergic G-protein coupled receptor. Nature 450, 383–387 (2007).
  3. Rasmussen, S. G. et al.  Crystal structure of the b2 adrenergic receptor–Gs protein complex. Nature 477,  549-557 (2011)