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The main problems found in designing drugs are those of optimizing the drug-target interaction and of avoiding the insurgence of resistance. We suggest a scheme for the design of inhibitors that can be used as leads for the development of a drug and that do not face either of these problems, and then apply it to the case of HIV-1-PR. It is based on the(More)
Metamorphic proteins such as lymphotactin are a notable exception of the empirical principle that structured natural proteins possess a unique three-dimensional structure. In particular, the human chemokine lymphotactin protein exists in two distinct conformations (one monomeric and one dimeric) under physiological conditions. In this work, we use a(More)
Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase are frequently found in many cancers. It has been suggested that changes in the equilibrium between its active and inactive conformations are linked to its oncogenic potential. Here, we quantify the effects of some of the most common single (L858R and T790M) and double(More)
In the laboratory, IM7 has been found to have an unusual folding mechanism in which an "on-pathway" intermediate with nonnative interactions is formed. We show that this intermediate is a consequence of an unusual cluster of highly frustrated interactions in the native structure. This cluster is involved in the binding of IM7 to its target, Colicin E7.(More)
The analysis of evolutionary amino acid correlations has recently attracted a surge of renewed interest, also due to their successful use in de novo protein native structure prediction. However, many aspects of protein function, such as substrate binding and product release in enzymatic activity, can be fully understood only in terms of an equilibrium(More)
c-Src and c-Abl are two closely related protein kinases that constitute important anticancer targets. Despite their high sequence identity, they show different sensitivities to the anticancer drug imatinib, which binds specifically to a particular inactive conformation in which the Asp of the conserved DFG motif points outward (DFG-out). We have analyzed(More)
Simplified Gō models, where only native contacts interact favorably, have proven useful to characterize some aspects of the folding of small proteins. The success of these models is limited by the fact that all residues interact in the same way so that the folding features of a protein are determined only by the geometry of its native conformation. We(More)
The Metropolis implementation of the Monte Carlo algorithm has been developed to study the equilibrium thermodynamics of many–body systems. Choosing small trial moves, the trajectories obtained applying this algorithm agree with those obtained by Langevin's dynamics. Applying this procedure to a simplified protein model, it is possible to show that setting(More)
Protein kinases play a key role in regulating cellular processes. Kinase dysfunction can lead to disease, making them an attractive target for drug design. The B-Raf kinase is a key target for the treatment of melanoma since a single mutation (V600E) is found in more than 50% of all malignant melanomas. Despite the importance of B-Raf in melanoma treatment,(More)
Proteins are dynamic molecules and their ability to adopt alternative conformations is central to their biological function. The structural and biophysical properties of transiently and sparsely populated states are, however, difficult to study and an atomic-level description of those states is challenging. We have used enhanced-sampling all-atom,(More)