Membrane Pharmacy Structure Dynamics 

Research group : Priv.Doz. Dr. Thomas Nawroth 

Molecular Motion  

in proteins and motile polymers

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Topics : Induced fit, Catalytic domain motion, Structural regulation, Motile polymers

Protein structure and dynamics

Proteins bearing catalytic functions, i.e. enzymes, especially those of cellular energy metabolism, motor proteins, key proteins of cell regulation and receptors are capable of molecular motion. This feature depicts the fact that a variety of proteins exist in more than one structure (fold). A structural flexibility is facilitated in membrane proteins by the hydrophobic effect (binding without localized forces, entropy-driven).

Induced fit

The flexibility of proteins  is generally a consequence of the composition of proteins from one ore more long chains of  polypeptides, which form a structure in space by folding. Between the fold elements, helices, beta-sheets and loops, mostly no covalent chemical bonds but weak interactions are present (hydrogen bridges, ionic pairs, hydrophobic interactions etc.). Thus most proteins are a rather "soft matter", which show some structural flexibilty when strong interactions to other molecules occur. This general small structural rearrangement inside enzymes is depicted by the "induced fit" model of substrate-enzyme interaction: In many cases the resting form of an enzyme fits not perfectly the structure of its substrate. The perfect molecular fit occurs only after substrate to protein binding by a structural rearrangement of the protein "wrapping arround the substrate". Nevertheless also in cases where no induced fit occurs small oscillations and motions of the protein structure contribute to the biological function, e.g. side group rotation of amino acids.

Catalytic domain motion

A second class of. larger strutural rearrangements is the displacement of whole structure domains, e.g. protein subunits, during a catalytic function or work. In this case the rearranged domain may be rather large, e.g. having >10,000 mass. The displacment distance is orders higher as in the induced fit case, e.g. 1 nm or more. The displacement is of transient nature, which means that it occurs only for a short time during catalysis. Then the protein is rearranged to its resting structure. Those catalytic domain motions are typical for bioenergetic proteins (energy converters) and molecular motors, e.g. muscle. In both cases the protein can store energy inside the rearranged structure. Those transient molecular motions can only be detected by time resolved methods, e.g. time resolved small angle scattering (TR-SAXS). A prrequsite is the synchronization of a macroscopic sample by a jump method, e.g. by sudden increase of the substrate concentration by rapid mixing with a stopped flow device or by photochemical activation of a burried form from caged-compounds or temperature jump. A succesful example is the estimation of transient structural changes in working F1ATPase during the reaction cycle of ATP hydrolysis.

Structural regulation

The structural regulation is a common principle of regulation processes in cells in the millisecond to minute time scale. At longer time (> 30 min) the regulation occors at the genetic level, i.e. by activation or down regulation of genes and subsequently the amount of special proteins beeing present in the cells. The structural regulation depicts a molecular regulation of proteins (enzymes) by switching over their structure from one stable fold to another, which differ in their biological activity. Enzymea having that feature are depicted as allosteric proteins. The structural switch can be triggered by reversible (loose) binding of an effector molecule or by chemical modification, e.g. phosphorylation, or proteolytic cleavage. Those regulative proteins are oftenly located at the end or beginning of a catalytic chain (regulative key function). Well known examples are the activation of cell metabolism by G-protein coupled hormone receptors recognizing external siganls, e.g. Adrenaline, or light in case of the visual system, and the structural regulation of ATP-synthase and its catalytic head, the F1ATPase.

Motile polymers

Polymers may consist of similar chemical components as proteins, but show mostly a lower degree of molecular order. This is a consequence of the actual techniques of polymerization, which can be improved, e.g. by topochemical polymerization or sequence specific block-condensation. Polymers of molecular order show improved properties, e.g. Kevlar (TM). Some polymers are sensitive to environment factors, e.g. temperature, light or pH. Thus the combination of technology and knowledge of proteins and polymers appears to be possible in the coming decade. The promising result would be polymers capable of active motion, i.e."motile polymers". Nevertheless before that two problems have to be solved: i) the energy input into the polymer system has to be established, for example by light as in the biological photosynthesis, or by electrical power, and ii) the analytic detection of molecular motion has to be developed in the nanosecond to millisecond range, which is the time scale of domain motions (the smaller, the faster). This requires the development of regioselective structure labeling techniques and the construction and long term funding of pulsed radiation sources for neutrons and X-ray / Synchrotron light, e.g. the pulsed free electron laser FEL.

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