Proteins conformational sampling

Q. Zheng, D. J. Kyle. Accuracy and reliability of the scaling-relaxation method for loop closure An evaluation based on extensive and multiple copy conformational samplings. Proteins. 1996, 24, 209-217. 

Conformational Adjustments The conformations of protein and ligand in the free state may differ from those in the complex. The conformation in the complex may be different from the most stable conformation in solution, and/or a broader range of conformations may be sampled in solution than in the complex. In the former case, the required adjustment raises the energy, in the latter it lowers the entropy in either case this effect favors the dissociated state (although exceptional instances in which the flexibility increases as a result of complex formation seem possible). With current models based on two-body potentials (but not with force fields based on polarizable atoms, currently under development), separate intra-molecular energies of protein and ligand in the complex are, in fact, definable. However, it is impossible to assign separate entropies to the two parts of the complex. 

Another approach is to run multiple MD simulations with different initial conditions. The recent work by Karplus and coworkers [19] observes that multiple trajectories with different initial conditions improve conformational sampling of proteins. They suggest that multiple trajectories should be used rather than a single long trajectory. 

Another practical limitation in complex applications lies in the fact that, if temperature is used as a control parameter, one needs to worry about the integrity of a system that is heated too much (e.g., water-membrane systems or a protein heated above its denaturation temperature). When issues such as those mentioned above are addressed, parallel tempering can be turned into a powerful and effective means of enhanced conformational sampling for free energies over a range of temperatures for various systems. 

The cost of a molecular dynamics (MD) free energy study depends very much on both the system and the goal of the study. If the goal is to reproduce qualitatively an experimental number and interpret it in terms of microscopic interactions, and if the systems of interest (e.g., native and mutant protein) are very similar, then only limited conformational sampling will be needed in most cases, and a few short runs with a small model may suffice. 

Rice, L.M. and Brunger, A.T. (1994) Torsion angle dynamics reduced variable conformational sampling enhances crystallographic structure refinement. Proteins 19,277-290. 

Faraldo-Gomez, J.D., Forrest, L.R., Baaden, M., Bond, P.J., Domene, C., Patargias, G., Cuthbertson, J., Sansom, M.S.P. Conformational sampling and dynamics of membrane proteins from 10-nanosecond computer simulations. Proteins Struct. Funct. Bioinformatics 2004, 57, 783-91. 

Although MC is an underutilized tool in the field of computational molecular biophysics, there are beneficial features that can be exploited, especially in conjunction with implicit solvent models. Specifically, MC has the potential of accessing length scales that are inaccessible to MD in complex phenomena like peptide aggregation or conformational sampling of intrinsically disordered proteins. 

The packing material first described for direct injection of biological samples was prepared by simply saturating the accessible adsorption sites of a Cis reversed-phase silica with human plasma proteins (105). After saturation, the human plasma proteins were denatured at the external surface, and their native conformation was destroyed. With this treatment, the proteins formed a hydrophilic layer with weak ion-exchange properties, which provided protection from contact with the sample proteins, whereas the alkyl ligands inside the pores remained unchanged and thus served for analyte retention. The retention behavior of the saturated phase did not alter with this treatment, but the efficiency was reduced dramatically. Such protein-coated columns have shown a lifetime of several months (106). 

An extension of the method that enables the steric shape of a protein site to be used as an additional constraint in the comparison of multiple potential pharmacophores of a protein site with a ligand has been developed, and is being commercialised as the DiR module of Chem-X. The method is equivalent to simultaneous 3D-database searching using multiple 3D pharmacophoric queries and steric constraints the advantage is that only one conformational sampling is necessary. 

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