Proteins first principles methods

First-principles Methods for Predicting Protein Structure... 

To summarise, first-principles methods have been successfully used to predict the naturally occurring conformations of small peptides but are not yet sufficiently reliable to predict accurately the structures of proteins, though in some cases the general fold of the molecule is quite similar to the native structure. However, as we shall see later in Section 10.8 lattice models have been very useful in helping to understand protein folding. 

The problems that occur when one tries to estimate affinity in terms of component terms do not arise when perturbation methods are used with simulations in order to compute potentials of mean force or free energies for molecular transformations simulations use a simple physical force field and thereby implicitly include all component terms discussed earlier. We have used the molecular transformation approach to compute binding affinities from these first principles [14]. The basic approach had been introduced in early work, in which we studied the affinity of xenon for myoglobin [11]. The procedure was to gradually decrease the interactions between xenon atom and protein, and compute the free energy change by standard perturbation methods, cf. (10). An (issential component is to impose a restraint on the... 

In an attempt to aid interpretation of the IR spectrum of MbCO we decided to model the full protein by use of a hybrid quantum mechanics/molecular mechanics approach (QM/MM), to evaluate changes in the CO stretching frequency for different protein conformations. The QM/MM method used [44] combines a first-principles description of the active center with a force-field treatment (using the CHARMM force field) of the rest of the protein. The QM-MM boundary is modeled by use of link atoms (four in the heme vinyl and propionate substituents and one on the His64 residue). Our QM region will include the CO ligand, the porphyrin, and the axial imidazole (Fig. 3.13). The vinyl and propionate porphyrin substituents were not included, because we had previously found they did not affect the properties of the Fe-ligand bonds (Section 3.3.1). It was, on the other hand, crucial to include the imidazole of the proximal His (directly bonded to the... 

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