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The example that we will consider is taken from a study which investigated the reaction mechanism of cAMP-dependent protein kinase using a mixture of QC, MM and QC/MM approaches. The reference may be found here. The enzyme is commonly referred to as PKA and it catalyzes the transfer of a phosphoryl group from adenosine triphosphate (ATP) to the serine sidechain of a target peptide or protein.

There are many criteria for selecting a structure for simulation but some relevant ones are:

  • Many studies, such as those looking at reaction mechanisms, require structures of high quality. This is determined by the resolution of the structure as well as by the absence of undefined regions.
  • It can be desirable to have a structure that resembles as much as possible the system that is to be simulated so as to minimize the amount of model building that is required. This means, for example, that the experimental structure should correspond to a protein with the correct (or almost correct) amino-acid sequence and have the appropriate bound co-factors and ligands.
  • The availability of experimental data, other than the structure, can be important for validating the simulation procedure. Examples include kinetic isotope effect measurements when studying reaction mechanisms and NMR order parameters when studying dynamics.

There will rarely be a single PDB structure that is "ideal" for a particular simulation study. Instead, it is often necessary to carry out a detailed comparison of several structures before a choice can be made. It is also common to employ multiple structures, either to construct a "hybrid" structure that conforms better to the system that is to be simulated than any of the experimental structures, or so that the results of simulations with different structures can be compared.

The structure chosen for this study was pig cAMP-dependent protein kinase with PDB entry 1CDK. It can be visualized using a wide-range of programs, some of which are indicated here. The structure is of reasonable resolution (2.0 Å) and, importantly, has ligands bound in the active site that resemble very closely those that are involved in the catalytic reaction. These include: two Mn2+ ions, as opposed to Mg2+ ions; an inactive twenty-residue peptide substrate in which the active serine is replaced by an alanine; and a 5'-adenyly-imido-triphosphate molecule that is very similar to ATP.