Scaling of folding properties in go models of proteins.
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ABSTRACT:
SUBMITTER: Cieplak M
PROVIDER: S-EPMC3456313 | biostudies-other | 2000 Dec
REPOSITORIES: biostudies-other
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Project description:Structure-based models are an efficient tool for folding studies of proteins since by construction their energy landscape is only minimal frustrated. However, their intrinsic drawback is a lack of structural flexibility as usually only one target structure is employed to construct the potentials. Hence, a Go-model may not capture differences in mutation-induced protein dynamics, if - as in the case of the disease-related A629P mutant of the Menkes protein ATP7A - the structural differences between mutant and wild type are small. In this work, we introduced three implementations of Go-models that take into account the flexibility of proteins in the NMR ensemble. Comparing the wild type and the mutant A629P of the 75-residue large 6th domain Menkes protein, we find that these new Go-potentials lead to broader distributions than Go-models relying on a single member of the NMR-ensemble. This allows us to detect the transient unfolding of a loosely formed β1β4-sheet in the mutant protein. Our results are consistent with previous simulations using physical force field and an explicit solvent, and suggests a mechanism by which these mutations cause Menkes disease. In addition, the improved Go-models suggest differences in the folding pathway between wild type and mutant, an observation that was not accessible to simulations of this 75-residue protein with a physical all-atom force field and explicit solvent.
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Project description:The Gō-like models of proteins are constructed based on the knowledge of the native conformation. However, there are many possible choices of a Hamiltonian for which the ground state coincides with the native state. Here, we propose to use experimental data on protein stretching to determine what choices are most adequate physically. This criterion is motivated by the fact that stretching processes usually start with the native structure, in the vicinity of which the Gō-like models should work the best. Our selection procedure is applied to 62 different versions of the Gō model and is based on 28 proteins. We consider different potentials, contact maps, local stiffness energies, and energy scales--uniform and nonuniform. In the latter case, the strength of the nonuniformity was governed either by specificity or by properties related to positioning of the side groups. Among them is the simplest variant: uniform couplings with no i, i + 2 contacts. This choice also leads to good folding properties in most cases. We elucidate relationship between the local stiffness described by a potential which involves local chirality and the one which involves dihedral and bond angles. The latter stiffness improves folding but there is little difference between them when it comes to stretching.
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Project description:BackgroundThe details of the folding mechanisms have not yet been fully understood for many proteins, and it is believed that the information on the folding mechanism of a protein is encoded in its amino acid sequence. β-trefoil proteins are known to have the same 3D scaffold, namely, a three-fold symmetric scaffold, despite the proteins' low sequence identity among superfamilies. In this study, we extract an initial folding unit from the amino acid sequences of irregular β-trefoil proteins by constructing an average distance map (ADM) and utilizing inter-residue average distance statistics to determine the relative contact frequencies for residue pairs in terms of F values. We compare our sequence-based prediction results with the packing between hydrophobic residues in native 3D structures and a Gō-model simulation.ResultsThe ADM and F-value analyses predict that the N-terminal and C-terminal regions are compact and that the hydrophobic residues at the central region can be regarded as an interaction center with other residues. These results correspond well to those of the Gō-model simulations. Moreover, our results indicate that the irregular parts in the β-trefoil proteins do not hinder the protein formation. Conserved hydrophobic residues on the β5 strand are always the interaction center of packing between the conserved hydrophobic residues in both regular and irregular β-trefoil proteins.ConclusionsWe revealed that the β5 strand plays an important role in β-trefoil protein structure construction. The sequence-based methods used in this study can extract the protein folding information from only amino acid sequence data, and well corresponded to 3D structure-based Gō-model simulation and available experimental results.
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