Protein force fields methodology

Effective application of empirical force field based methodologies is based, in part, on the accuracy of the force field. The present article describes the functional forms of force fields used for the study of proteins. This is followed by information on the methods used for optimization of the force field parameters and how those parameters are tested. A brief conclusion includes a summary and an outlook of theoretical developments which may influence future protein force fields. The present article does not present a rigorous comparison of currently available force fields. Rather, it emphasizes the approaches used in the optimization and testing of protein force fields in order to allow the reader to select the most appropriate force field for the particular problem they are addressing. 

The QM/MM and ab initio methodologies have just begun to be applied to challenging problems involving ion channels [73] and proton motion through them [74]. Reference [73] utilizes Hartree-Fock and DFT calculations on the KcsA channel to illustrate that classical force fields can fail to include polarization effects properly due to the interaction of ions with the protein, and protein residues with each other. Reference [74] employs a QM/MM technique developed in conjunction with Car-Parrinello ab initio simulations [75] to model proton and hydroxide ion motion in aquaporins. Due to the large system size, the time scale for these simulations was relatively short (lOps), but the influences of key residues and macrodipoles on the short time motions of the ions could be examined. 

When addressing problems in computational chemistry, the choice of computational scheme depends on the applicability of the method (i.e. the types of atoms and/or molecules, and the type of property, that can be treated satisfactorily) and the size of the system to be investigated. In biochemical applications the method of choice - if we are interested in the dynamics and effects of temperature on an entire protein with, say, 10,000 atoms - will be to run a classical molecular dynamics (MD) simulation. The key problem then becomes that of choosing a relevant force field in which the different atomic interactions are described. If, on the other hand, we are interested in electronic and/or spectroscopic properties or explicit bond breaking and bond formation in an enzymatic active site, we must resort to a quantum chemical methodology in which electrons are treated explicitly. These phenomena are usually highly localized, and thus only involve a small number of chemical groups compared with the complete macromolecule. 

Although there are a wide variety of models for simulating protein folding, we have chosen a fairly simple force field and tethered-bead model to demonstrate the optimal histogram methodology. The basic model was first described by Honeycutt and Thirumalai to model the folded states of / -barrel structures [14,15] and has since been re-parameterized by us to model a-helical-type structures as well [16]. The specific sequence studied here... 

Maple, J. R., et al, A polarizable force field and continuum solvation methodology for modeling of protein-ligand interactions. /. Chem. Theor. Comput, 2005.1(4), 694-715. 

Thus, next our methodology was used to carry out force-field molecular dynamics simulations on the same system as used in the experiments, that is a computational model of the mutated 27th immunoglobulin-like domain of cardiac titin (127) and we have succesfully proved that the mechanism extracted from the minimal model is responsible for the experimental findings reported for the protein. 

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