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Phys. Biol. 14 (2017) 010402 doi:10.1088/1478-3975/aa559f


Physical concepts in biology—past and future

6 December 2016
Hans Frauenfelder
23 December 2016 Physics Division, Los Alamos National Laboratory, Los Alamos, NM 87545, United States of America
8 February 2017

The challenge Conformational substates

Biomolecules do not exist in unique structures;
Biologists and physicists look at biological systems with they assume an extremely large number of different
different focus. Consider for example myoglobin from conformations. Each conformational substate is as a
whales and horses. The two proteins look similar, but point in a high-dimensional conformation space that
differ in their amino acid sequences and structures. describes the position of each atom in the protein.
They also differ for instance important in their pressure
dependences for the binding of oxygen and carbon Free-energy landscape
monoxide [1], likely because whales dive, but horses The free-energy landscape characterizes the energetics
do not. Biologists and biophysicists are interested how in the conformational space. Each substate is a potential
the different primary sequences lead to the different well in the landscape. Changing conformation means
functions. Biological physicists are more interested moving from well to well over one or many potential
in the general features that unify all myoglobins, that barriers. Experiments have shown that the energy
apply universally to all biomolecules, and that may lead landscape is organized in a hierarchy, there are wells
to new physics. within wells within wells. Little is known in detail about
The role of concepts and laws will be increasingly the landscape. Probably the best studied case is the
crucial because of the rapid increase in the number of folding funnel, where computations and experiments
relevant publications. In 1950, there were about 100 have led to progress in the understanding of protein
papers per year published on protein dynamics. In 2010 folding [5].
the number had risen to about 100 000 yr−1 and was
increasing nearly exponentially. Reading and evaluating Dynamics and fluctuations
even a small fraction of these publications is becoming To perform functions, proteins must dance in the
more difficult. Universal concepts and laws are needed energy landscape. The dance is not spontaneous, it is
for the understanding of the dynamics and functions of induced by fluctuations. Three types of fluctuations
ever more complex biosystems. Here I sketch important are important: thermal vibrations, fluctuations in the
concepts and laws found during the past approximately hydration shell, and fluctuations in the bulk solvent.
40 years, with a very personal view. Understanding the dynamics is only at a beginning. We
are probably at the state of the Bohr model in atomic
The past physics.

Biophysics and biological physics entered a new Experimental tools

era when John Kendrew elucidated the structure of Physics has provided many of the tools crucial for
myoglobin and Max Perutz determined the structure biology. When I started work as a graduate student
of hemoglobin. The beautiful 3D pictures of the two in nuclear physics, most of the equipment, from
proteins gave the impression that the proteins were like Geiger–Müller counters to amplifiers with vacuum
little crystals with rigid unique structures. Far-sighted tubes was home-made. The data were evaluated using
scientists, such as Linderstrom-Lang and Schellman, a hand-driven mechanical calculator. At present, most
had pointed out earlier that biomolecules could not instruments are commercially made and the range
be in unique structures, but their insight was largely of tools is immense, from large accelerators to high-
overlooked. Unambiguous support for the view of performance computers.
fluctuating inhomogeneous proteins came from low-
temperature flash photolysis [2] and x ray diffraction The role of biological physics
[3] experiments. The main concepts coming from these During the past few decades, the view of physicists
and a very large number of additional experiments and towards work in biology has changed. Physicists who
computations can be described as follows [4]. are interested in biological problems no longer have

© 2017 IOP Publishing Ltd

Phys. Biol. 14 (2017) 010402 H Frauenfelder

to leave the physics department. Biological physics experimental, and theoretical work can produce a
has become an accepted part of physics and physics view of the landscape with predictive power. NSF
departments. The International Union of Physics and other agencies can continue to foster work on
and Applied Physics (IUPAP) has a commission on protein dynamics and function that combines theory,
biological physics and the American Physical Society experiment, and computing. While the theoretical
has a division of Biological Physics. advances will continue to spring from the brains
of individual scientists, the experimental work will
The importance of program managers increasingly involve large facilities such as SLAC and
Without the long-term support from the program the European spallation source. Program managers will
managers much of the work would not have been be important in coordinating and supporting research
possible. Their understanding was crucial, particularly involving many groups.
when the exciting results had little relation to what was
initially proposed.
The future [1] Frauenfelder H et al 1990 J. Phys. Chem. 94 1024
[2] Austin R H et al 1975 Biochemistry 14 5355
[3] Frauenfelder H, Petsko G A and Tsernouglou D 1979 Science
Dynamics and function of proteins and nucleic
280 1979
acids are to a large degree determined by the energy [4] Frauenfelder H, Wolynes P G and Austin R H 1999 Rev. Mod.
landscape and by fluctuations. The two are still largely Phys. 71 S419
unexplored. I expect that coordinated computational, [5] Wolynes P G 2005 Phil. Trans. R. Soc. A 363 453