Since the first pioneering spectroscopic studies of amino acids and small peptides in the gas phase by Don Levy at the University of Chicago, a rapidly increasing number of molecular spectroscopists have extended their horizons to include structural (and a few dynamical) studies of isolated and clustered bio-active molecules, biomolecular building blocks and larger molecular assemblies involved in the biophysics and biochemistry of living bodies, exploiting methods previously employed only for "simple" molecules. A suite of powerful strategies has now evolved which employs a combination of experimental techniques such as laser ablation for transferring them into the gas phase; rapid cooling in a free jet expansion or in large helium droplets to stabilize their conformers and/or clusters; a highly selective and sensitive armory of i.r. and u.v. laser-based optical spectroscopies, coupled with mass spectrometry, to probe their structural landscapes; and the ready accessibility of powerful ab initio quantum chemical computational codes for their interpretation. Fast quantum calculation and optical spectroscopic techniques are now providing access to neurotransmitters and enzyme blockers, amino acids and peptides, sugars and glycopeptides, DNA bases and nucleosides—all studied under experimental conditions previously used only for simpler molecules. Our review conveyed the excitement generated by linking chemical biology with the quantitative strategies of experimental chemical physics and computational quantum chemistry, which is providing the classic, non-linear interaction needed for a new burst of creative research.

  Does it describe a new discovery or new methodology that's useful to others?

The article provided a survey of "where things were at" at the start of the millennium and a prospectus for the future.

  How did you become involved in this research?

We were inspired first by Don Levy’s ground-breaking early spectroscopic studies of small peptides and amino acids reported in the mid-eighties and then by sheer "cussedness": how far forward could the "molecular size horizon" be pushed beyond the world of small molecules towards systems of "real" biological significance? The answer: very much further than we first anticipated and way beyond the expectations of many of our peers.

  Could you summarize the significance of your paper in layman's terms?

Bio-molecular shapes and conformations are controlled by a delicate balance between the forces that operate through their chemical bonds—determining their skeletal structures—and those that operate through "non-bonded" interactions, particularly hydrogen-bonding. These operate between neighboring groups or local electrical charges within the molecule, or between the molecule and its environment, particularly water—Nature's favorite solvent. In the last few years, the combination of laser-based spectroscopy and mass spectrometry, coupled with ab initio computation has revealed the "structural images" of individual biomolecular conformers and their mass-selected, often hydrogen-bonded, molecular clusters, isolated in the gas phase and/or frozen in a low temperature environment. Theory and experiment enjoy a symbiotic relationship—their interaction is a co-operative one. Theory provides the "à la carte menu" of structural possibilities; experimental observation and analysis tells us which ones are actually chosen. The strategy borrowed from the world of chemical physics, although reductionist, recognizes that complexity grows out of simplicity, i.e., you need bricks to build the house.

John Simons
Dr Lee's Professor of Chemistry Emeritus
Oxford University
Oxford, UK