Related papers: Resistance proof, folding-inhibitor drugs
Learning how proteins fold will hardly have any impact in the way conventional -- active site centered -- drugs are designed. On the other hand, this knowledge is proving instrumental in defining a new paradigm for the identification of…
While all the information required for the folding of a protein is contained in its amino acid sequence, one has not yet learned how to extract this information to predict the three--dimensional, biologically active, native conformation of…
One of the main problems of drug design is that of optimizing the drug--target interaction. In the case in which the target is a viral protein displaying a high mutation rate, a second problem arises, namely the eventual development of…
Drug resistance to HIV-1 Protease involves accumulation of multiple mutations in the protein. Here we investigate the role of these mutations by using molecular dynamics simulations which exploit the influence of the native-state topology…
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…
Being HIV-1-PR an essential enzyme in the viral life cycle, its inhibition can control AIDS. Because the folding of single domain proteins, like HIV-1-PR is controlled by local elementary structures (LES, folding units stabilized by…
What can cells gain by using disordered, rather than folded, proteins in the architecture of their skeleton? Disordered proteins take multiple co-existing conformations, and often contain segments which act as random-walk-shaped polymers.…
Natural protein molecules are exceptional polymers. Encoded in apparently random strings of amino-acids, these objects perform clear physical tasks that are rare to find by simple chance. Accurate folding, specific binding, powerful…
Using the Dominant Reaction Pathways method, we perform an ab-initio quantum-mechanical simulation of a conformational transition of a peptide chain. The method we propose makes it possible to investigate the out-of-equilibrium dynamics of…
Amphipathic peptides are considered promising antibiotics because of their ability to form pores in bacterial membranes. In two companion papers, we analyzed both experimentally and theoretically the mechanisms and consequences of the…
Antimicrobial peptides (AMPs) have intrigued researchers for decades due to the contradiction between their high potential against resistant bacteria and the inability to find a structure-function relationship for the development of an…
The extent of coupling between the folding of a protein and its binding to a substrate varies from protein to protein. Some proteins have highly structured native states in solution, while others are natively disordered and only fold fully…
Natural protein sequences that self-assemble to form globular structures are compact with high packing densities in the folded states. It is known that proteins unfold upon addition of denaturants, adopting random coil structures. The…
Being the HIV-1 Protease (HIV-1-PR) an essential enzyme in the viral life cycle, its inhibition can control AIDS. The folding of single domain proteins, like each of the monomers forming the HIV-1-PR homodimer, is controlled by local…
A reduced model, which can fold both helix and sheet structures, is proposed to study the problem of protein folding. The goal of this model is to find an unbiased effective potential that has included the effects of water and at the same…
Making use of a simplified model for protein folding, it can be shown that conformations which are particularly stable when their energy is minimized with respect to amino acid sequence (in the sense that they display a large energy gap to…
We investigated the role of peptide folding stability in peptide immunogenicity. It was the aim of this thesis to implement a stability criterion based on energy computations using an AMBER force field, and to test the implementation with a…
How proteins fold remains a central unsolved problem in biology. While the idea of a folding code embedded in the amino acid sequence was introduced more than 6 decades ago, this code remains undefined. While we now have powerful predictive…
Peptide-based drugs can bind to protein interaction sites that small molecules often cannot, and are easier to produce than large protein drugs. However, designing effective peptide binders is difficult. A typical peptide has an enormous…
A central question is how the conformational changes of proteins affect their function and the inhibition of this function by drug molecules. Many enzymes change from an open to a closed conformation upon binding of substrate or inhibitor…