Advanced material Computer simulation of enzyme structure and reaction mechanism

The phenomenal increase in computer power over the last 30 years has made it possible to simulate the behaviour of molecules numerically. For this purpose atoms are placed in virtual space, guided for example by the data from X-ray crystallography or NMR-studies. Then there exist forces between these atoms, for example from stretching, compression or torsion of covalent bonds, electrostatic interaction between charged or polarised groups, van der WAAls-attraction and so on. PAuu-repulsion prevents atoms from getting to close to each other. These forces can be modelled as mechanical springs between the particles, the resulting movements can then be calculated by numerical integration of Newtons laws of motion (see page 125 for a discussion of numerical integration). This is called molecular dynamics.

This way it is possible to refine models of protein structure, if their resolution is not high enough. The virtual molecule is exposed to a high temperature, with rapid movement of the atoms. As the temperature is reduced, movement becomes slower and atoms take the position of minimal energy (simulated annealing).

It is also possible to simulate the behaviour of molecules during a reaction, for example the behaviour of water molecules during their passage through aquaporin molecules [28]. The aquaporin molecule was embedded into a lipid membrane, which was immersed in water. The model totalled more than 100 000 atoms. Simulation of this system took several months of calculation time on a supercomputer, resulting in a film that showed the passage of water molecules through the aquaporin. Speed of passage agreed well with measured values, thus the model is probably correct.

The "dance of water molecules" through the aquaporin channel is made possible by the fact that whenever hydrogen bonds need to be broken to allow passage through the narrow channel they are replaced by other hydrogen bonds. Thus the activation energy for water transport is low and the speed can be high. In addition, the aquaporin molecule contains two potential barriers which prevent the passage of both positively and negatively charged ions.

Most residues in the channel wall are hydrophobic to allow water to move through the channel quickly, however, there are 4 water binding pockets with hydrophilic residues as well. These lower the energy required for breaking the hydrogen bonds with other water molecules, which is necessary to transport water molecules in single file.

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