C6. Commission on Biological Physics

Report to the 1999 General Assembly for 1996-99

Officers 1996-1999:

Chairman: N. Go, Japan

Vice Chairman: M. Bloom, Canada

Secretary: A. Ehrenberg Sweden,

Members:

R.H. Austin, USA

V.I. Goldanskii, Russia

Z. Kam, Israel

P.F. Lindley, U.K

P. Ormos, Hungary

F.G. Parak, Germany

G. Parisi, Italy

M. Peyrard, France

A. Saran, India

X. Shen, China

Associate Members 94-97:

T.V. Ramakrishnan, India

A. Rich, USA

M. Virasoro, Italy

ACTIVITIES:

Frequent contacts and discussions within C6 have been via e-mail. Plans have been made for establishing a Commission Home Page. C6 has had one meeting with members in person, in Santa Fé, September 23, 1998.

Since the subject of Biological Physics as academic curriculum is very new and has as many forms and facets as there are teaching courses practised at the various universities, C6 has decided to encourage that the outlines of these courses are published in Home Pages of the departments, which should be available also via the Home Page of C6. This will facilitate contacts and exchange of teachers between the various centers, and stimulate the development of the whole field.

The Third Symposium on Biological Physics, sponsored by the Commission, was held in Santa Fé, N.M., USA, September 24-28, 1998. The number of participants was more than 130, and 17 countries were represented. This symposium covered a broader scope of the field than the previous meetings.

The next symposium is scheduled for 2001, to be organized by Prof. N. Go in Kyoto, Japan.

Two conferences planned to take place during 1999 are sponsored by C6: "Fluctuations in Biological Systems" in Sweden, and "Protein Dynamics" in USA.

NEW DEVELOPMENTS IN THE FIELD:

Biology is now entering into the era of structural biology, where various biological functions are studied not only on the level of genetic information but also on the level of three-dimensional atomic-resolution structures of molecular machineries. Behind this change of the scene is the fact that experimental determination of three-dimensional structures of biopolymers is taking place at an accelerated rate due to the development of such technologies as sample preparation using genetic manipulation, X-ray crystallography and nuclear magnetic resonance (NMR). Importance of genetic information has been very persuasively demonstrated by the explosion of the molecular biology based on it. However, its success is based on the logic of one-to-one correspondence between a gene and an elementary function, a logic which skips the intermediate, the protein. The era of structural biology means that we are now able to study how biological functions are performed by observing the behaviors of real machineries responsible for them.

In this new era, the relation between physics and biology has become tighter in two ways. At first, observation of three-dimensional structures and their dynamic behaviors requires technologies which are basically physical in nature. Here physics is assisting biology by providing important technologies. At second, when studying biological phenomena, after the stage of identifying specific molecules responsible for them, we may now ask questions of physical nature and perform observations of the dynamic behavior of real molecular machineries. The behaviors observed do not violate the known laws of physics, but it is becoming more and more clear that we need new concepts to understand them well. This is natural, because biological systems are much more complex than, and hence different from, systems conventionally studied in physics. The above two aspects will be discussed below.

New physical technologies for biology

1. Methods used for structure determination

In the physiological environment, protein molecules assume complex three-dimensional structures that are specific to their amino-acid sequence, and only when they assume their sequence-specific three-dimensional structure, they are able to perform their biological functions. Therefore, the starting point of the structural biology study is the elucidation of the three-dimensional structure at the atomic resolution. In practice X-ray crystallography and NMR and more recently electron microscopy and neutron scattering are used to determine three-dimensional structures of biopolymers and their complexes. In the field of X-ray crystallography, the synchrotron as source of intense radiation is becomig increasingly more important, and contributing to opening up of new ways of structure determination. Rapid technological developments are also taking place in NMR, electron microscopy and neutron scattering.

2. Observation and manipulation of one-molecule systems

The three-dimensional structures determined by the methods described above are averaged ones in a certain state such as in a crystalline state. In the physiological state they are undergoing conformational fluctuations due to thermal motions. When a system of biopolymers perform its function, generally they go through a more-or-less specific series of dynamical steps. Identification of such steps is essential for elucidation of molecular mechanism of biological functions. Usually, each of the dynamical steps is a process characterized by a corresponding activated state. Going over an activated state is inevitably a stochastic process. This stochastic nature of the dynamical process presents a difficult problem for experimental identification of intermediate steps. Usually a physical observation is done for an ensemble of molecules, which then yields only an averaged picture. Even when a number of identical molecular systems are set to start a certain biological function consisting of a number of elementary molecular steps in a synchronized manner, the steps of action in the constituent systems become very rapidly desynchronized. A picture obtained by averaging over such a desynchronized ensemble of systems is quite poor. To escape from this difficulty, it is desirable to make physical observation of a system consisting of as small a number of molecules as possible, ultimately just one molecule. This is the direction of many recent studies in biological physics. There are by now many techniques, by which observation and manipulation of a single molecular system has been successfully achieved. The physical background behind such single molecule technologies is already quite diverse. This means that a wide variety of experimental methods will be employed in this important field in the near future. They in turn would contribute to enrich the physical understanding of biological phenomena.

New concepts for biological systems

In the new era of structural biology, an increasing number of biological phenomena will be studied from a physical point of view. Will new concepts become necessary or useful in such studies? The answer appears to be yes. As an example of such a case, the problem of protein folding will be discussed below.

As mentioned earlier, protein molecules assume in their physiological environment complex three-dimensional structures that are specific to their amino-acid sequence. After a polypeptide chain with a specific amino acid sequence is synthesized in a cell, in general no extra information is needed for it to fold into the specific three-dimensional structure of the native state. Conceptually this is understood as the native state being an equilibrium state with the global minimum of free energy. When the environmental condition is changed beyond a certain extent, proteins in the native state are known to undergo transition into so-called denatured states. This is a phenomenon similar to order-disorder transitions such as solid-liquid phase transitions. Therefore the native state should be characterized as a state with a distinctively low energy to cope with a large entropy term that can be decreased if the structure is unfolded into random states.Up to this point, basic experimental facts about protein folding are described together with their simple physical interpretations. Even though both facts and interpretations appear to be simple and innocent, they are in fact very peculiar. A protein molecule is a chain heteropolymer with a specific amino acid sequence. Its potential energy surface in a high dimensional conformational space should have a very large number of local minima reflecting the heterogeneity of the orientations and contacts of the various amino acid sidechains. It is highly unlikely that there is a unique state with a distinctively low energy, which, if it exists, would become a native state. However, if the various energy components constituting the potential energy are mutually consistent in a particular conformational state, such a state would have a distinctively low energy. In the native state conformations of proteins, this consistency of various constituent energy terms is in fact found to be largely satisfied. This finding is summarized as a consistency principle (also referred to as a principle of minimum frustration) that is satisfied by the native states of proteins. It means that amino acid sequences that satisfy this principle are selected during the evolution and are used as proteins. Therefore the consistency principle is a principle pertaining to the history of evolution, but at the same time it is the principle which explains physico-chemical properties of proteins such as uniqueness of the native state conformation and character of folding-unfolding transitions that are similar to order-disorder phase transitions.

Above an example was given of a concept that is unique to a biological system and useful for understanding it. Biological systems are generally extremely complex but yet well organized and effective in their function. Various new concepts are being proposed and developed in order to understand these enormously complex biological systems.

N. Go Chair