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 Phys. Biol. 14 (2017) 010402
EDITORIAL
Physical concepts in biology—past and future
RECEIVED
6 December 2016
ACCEP TED FOR PUBLICATION
Hans Frauenfelder
23 December 2016 Physics Division, Los Alamos National Laboratory, Los Alamos, NM 87545, United States of America
PUBLISHED E-mail: hansfrauenfelder@me.com
8 February 2017
The challenge
Biologists and physicists look at biological systems with
different focus. Consider for example myoglobin from
whales and horses. The two proteins look similar, but
differ in their amino acid sequences and structures.
They also differ for instance important in their pressure
dependences for the binding of oxygen and carbon
monoxide [1], likely because whales dive, but horses
do not. Biologists and biophysicists are interested how
the different primary sequences lead to the different
functions. Biological physicists are more interested
in the general features that unify all myoglobins, that
apply universally to all biomolecules, and that may lead
to new physics.
The role of concepts and laws will be increasingly
crucial because of the rapid increase in the number of
relevant publications. In 1950, there were about 100
papers per year published on protein dynamics. In 2010
the number had risen to about 100 000 yr−1 and was
increasing nearly exponentially. Reading and evaluating
even a small fraction of these publications is becoming
more difficult. Universal concepts and laws are needed
for the understanding of the dynamics and functions of
ever more complex biosystems. Here I sketch important
concepts and laws found during the past approximately
40 years, with a very personal view.
The past
Biophysics and biological physics entered a new
era when John Kendrew elucidated the structure of
myoglobin and Max Perutz determined the structure
of hemoglobin. The beautiful 3D pictures of the two
proteins gave the impression that the proteins were like
little crystals with rigid unique structures. Far-sighted
scientists, such as Linderstrom-Lang and Schellman,
had pointed out earlier that biomolecules could not
be in unique structures, but their insight was largely
overlooked. Unambiguous support for the view of
fluctuating inhomogeneous proteins came from low-
temperature flash photolysis [2] and x ray diffraction
[3] experiments. The main concepts coming from these
and a very large number of additional experiments and
computations can be described as follows [4].
© 2017 IOP Publishing Ltd
doi:10.1088/1478-3975/aa559f
Conformational substates
Biomolecules do not exist in unique structures;
they assume an extremely large number of different
conformations. Each conformational substate is as a
point in a high-dimensional conformation space that
describes the position of each atom in the protein.
Free-energy landscape
The free-energy landscape characterizes the energetics
in the conformational space. Each substate is a potential
well in the landscape. Changing conformation means
moving from well to well over one or many potential
barriers. Experiments have shown that the energy
landscape is organized in a hierarchy, there are wells
within wells within wells. Little is known in detail about
the landscape. Probably the best studied case is the
folding funnel, where computations and experiments
have led to progress in the understanding of protein
folding [5].
Dynamics and fluctuations
To perform functions, proteins must dance in the
energy landscape. The dance is not spontaneous, it is
induced by fluctuations. Three types of fluctuations
are important: thermal vibrations, fluctuations in the
hydration shell, and fluctuations in the bulk solvent.
Understanding the dynamics is only at a beginning. We
are probably at the state of the Bohr model in atomic
physics.
Experimental tools
Physics has provided many of the tools crucial for
biology. When I started work as a graduate student
in nuclear physics, most of the equipment, from
Geiger–Müller counters to amplifiers with vacuum
tubes was home-made. The data were evaluated using
a hand-driven mechanical calculator. At present, most
instruments are commercially made and the range
of tools is immense, from large accelerators to high-
performance computers.
The role of biological physics
During the past few decades, the view of physicists
towards work in biology has changed. Physicists who
are interested in biological problems no longer have
Phys. Biol. 14 (2017) 010402
to leave the physics department. Biological physics
has become an accepted part of physics and physics
departments. The International Union of Physics
and Applied Physics (IUPAP) has a commission on
biological physics and the American Physical Society
has a division of Biological Physics.
The importance of program managers
Without the long-term support from the program
managers much of the work would not have been
possible. Their understanding was crucial, particularly
when the exciting results had little relation to what was
initially proposed.
The future
Dynamics and function of proteins and nucleic
acids are to a large degree determined by the energy
landscape and by fluctuations. The two are still largely
unexplored. I expect that coordinated computational,
H Frauenfelder
experimental, and theoretical work can produce a
view of the landscape with predictive power. NSF
and other agencies can continue to foster work on
protein dynamics and function that combines theory,
experiment, and computing. While the theoretical
advances will continue to spring from the brains
of individual scientists, the experimental work will
increasingly involve large facilities such as SLAC and
the European spallation source. Program managers will
be important in coordinating and supporting research
involving many groups.
References
[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
280 1979
[4] Frauenfelder H, Wolynes P G and Austin R H 1999 Rev. Mod.
Phys. 71 S419
[5] Wolynes P G 2005 Phil. Trans. R. Soc. A 363 453