اشترك بالحزمة الذهبية واحصل على وصول غير محدود شمرا أكاديميا
تسجيل مستخدم جديدCrucial stages of protein folding through a solvable model: predicting target sites for enzyme-inhibiting drugs
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An exactly solvable model based on the topology of a protein native state is applied to identify bottlenecks and key-sites for the folding of HIV-1 Protease. The predicted sites are found to correlate well with clinical data on resistance to FDA-approved drugs. It has been observed that the effects of drug therapy are to induce multiple mutations on the protease. The sites where such mutations occur correlate well with those involved in folding bottlenecks identified through the deterministic procedure proposed in this study. The high statistical significance of the observed correlations suggests that the approach may be promisingly used in conjunction with traditional techniques to identify candidate locations for drug attacks.
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A general strategy is described for finding which amino acid sequences have native states in a desired conformation (inverse design). The approach is used to design sequences of 48 hydrophobic and polar aminoacids on three-dimensional lattice structu
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A theoretical model for the folding of proteins containing disulfide bonds is introduced. The model exploits the knowledge of the native state to favour the progressive establishment of native interactions. At variance with traditional approaches bas
ed on native topology, not all native bonds are treated in the same way; in particular, a suitable energy term is introduced to account for the special strength of disulfide bonds (irrespective of whether they are native or not) as well as their ability to undergo intra-molecular reshuffling. The model thus possesses the minimal ingredients necessary to investigated the much debated issue of whether the re-folding process occurs through partially structured intermediates with native or non-native disulfide bonds. This strategy is applied to a context of particular interest, the re-folding process of Hirudin, a thrombin-specific protease inhibitor, for which conflicting folding pathways have been proposed. We show that the only two parameters in the model (temperature and disulfide strength) can be tuned to reproduce well a set of experimental transitions between species with different number of formed disulfide. This model is then used to provide a characterisation of the folding process and a detailed description of the species involved in the rate-limiting step of Hirudin refolding.
We develop a theoretical approach to the protein folding problem based on out-of-equilibrium stochastic dynamics. Within this framework, the computational difficulties related to the existence of large time scale gaps in the protein folding problem a
re removed and simulating the entire reaction in atomistic details using existing computers becomes feasible. In addition, this formalism provides a natural framework to investigate the relationships between thermodynamical and kinetic aspects of the folding. For example, it is possible to show that, in order to have a large probability to remain unchanged under Langevin diffusion, the native state has to be characterized by a small conformational entropy. We discuss how to determine the most probable folding pathway, to identify configurations representative of the transition state and to compute the most probable transition time. We perform an illustrative application of these ideas, studying the conformational evolution of alanine di-peptide, within an all-atom model based on the empiric GROMOS96 force field.
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hat rules the interaction between different kinds of residues. If the interaction matrix is dominated by the hydrophobic effect (Miyazawa Jernigan like matrix), this distribution is very simple - all the hot sites can be found at the positions with maximum number of closest nearest neighbors (bulk). If random or nonlinear corrections are added to such an interaction matrix the distribution pattern changes. The rising of collective effects allows the hot sites to be found in places with smaller number of nearest neighbors (surface) while the general trend of the hot sites to fall into a bulk part of a conformation still holds.
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