Molecular dynamic simulations protein flexibility

Mangoni M, Roccatano D, Di Nola A. 1999. Docking of flexible ligands to flexible receptors in solution by molecular dynamics simulation. Proteins 35(2) 153-162. 

Wang, T, Wade, R. Implicit solvent models for flexible protein-protein docking by molecular dynamics simulation. Proteins 2003, 50,158-69. 

Of great interest to the molecular biologist is the relationship of protein form to function. Recent years have shown that although structural information is necessary, some appreciation of the molecular flexibility and dynamics is essential. Classically this information has been derived from the crystallographic atomic thermal parameters and more recently from molecular dynamics simulations (see for example McCammon 1984) which yield independent atomic trajectories. A diaracteristic feature of protein crystals, however, is that their diffraction patterns extend to quite limited resolution even employing SR. This lack of resolution is especially apparent in medium to large proteins where diffraction data may extend to only 2 A or worse, thus limiting any analysis of the protein conformational flexibility from refined atomic thermal parameters. It is precisely these crystals where flexibility is likely to be important in the protein function. 

The main conclusion drawn from the MD simulations is that the proteins are highly flexible. The parts of the proteins that have high B-factors in the crystal structure also show great flexibility in the dynamics. The same regions are flexible in both runs, but the internal correlations of movements differ. This is reflected in the CPCA score plot the snapshots of each of the two CYP2C9 runs and the X-ray structures showed up in a different quadrant and did not overlap at any time point of the simulation. Thus, the molecular dynamics simulations cover a different CPCA space from the crystal structures with and without substrate bound, independent of the different starting structures. 

Maximal surface complementarity between two molecules is reached when O g is maximal while V g takes a minimum value. The new technology has been tested in an initial application by matching the surfaces of the two flexible proteins tryspin and PTI. In this application the membership functions and x,y were calculated from molecular dynamic simulations similar to those reported earlier. It turns out that the structure of the trypin-PTI complex is very close to that which was found in x-ray studies. 

Molecular dynamics simulation methods are currently the most popular approaches. This method is for the analysis of protein flexibility and dynamic properties of molecular systems. With respect to docking, these simulations could provide a realistic view of the docking process, however, these calculations are still out of reach. Therefore, dynamical simulations during the docking process are limited to the protein-ligand complexes. Molecular dynamical simulations are often... 

Gsponer J, Ferrara P, Caflisch A (2001) Flexibility of the murine prion protein and its Asp 178 Asn mutant investigated by molecular dynamics simulations. J Mol Graph Model 20 169... 

D. Bassolino-Klimas, R. Tejero, S. R. Krystek, W. J. Metzler, G. T. Montelione, R. E. Bruccoleri. Simulated annealing with restrained molecular dynamics using a flexible restraint potential theory and evaluation with simulated NMR constraints. Protein Sci. 1996, 5, 593-603. 

All of the simulation approaches, other than harmonic dynamics, include the basic elements that we have outlined. They differ in the equations of motion that are solved (Newton s equations, Langevin equations, etc.), the specific treatment of the solvent, and/or the procedures used to take account of the time scale associated with a particular process of interest (molecular dynamics, activated dynamics, etc.). For example, the first application of molecular dynamics to proteins considered the molecule in vacuum.15 These calculations, while ignoring solvent effects, provided key insights into the important role of flexibility in biological function. Many of the results described in Chapts. VI-VIII were obtained from such vacuum simulations. Because of the importance of the solvent to the structure and other properties of biomolecules, much effort is now concentrated on systems in which the macromolecule is surrounded by solvent or other many-body environments, such as a crystal. 

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