arXiv subjects

F. Simona

Publications and source records attributed to F. Simona.

4 recordsLinked to original sources

arXiv2005

Design of HIV-1-PR inhibitors which do not create resistance: blocking the folding of single monomers

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 resistance. We wish to suggest a scheme for the design of non--conventional drugs which do not face any of these problems and apply it to the case of HIV--1 protease. It is based on the knowledge that the folding of single--domain proteins, like e.g. each of the monomers forming the HIV--1--PR homodimer, is controlled by local elementary structures (LES), stabilized by local contacts among hydrophobic, strongly interacting and highly conserved amino acids which play a central role in the folding process. Because LES have evolved over myriads of generations to recognize and strongly interact with each other so as to make the protein fold fast as well as to avoid aggregation with other proteins, highly specific (and thus little toxic) as well as effective folding--inhibitor drugs suggest themselves: short peptides (or eventually their mimetic molecules), displaying the same amino acid sequence of that of LES (p--LES). Aside from being specific and efficient, these inhibitors are expected not to induce resistance: in fact, mutations which successfully avoid their action imply the destabilization of one or more LES and thus should lead to protein denaturation. Making use of Monte Carlo simulations within the framework of a simple although not oversimplified model, which is able to reproduce the main thermodynamic as well as dynamic properties of monoglobular proteins, we first identify the LES of the HIV--1--PR and then show that the corresponding p--LES peptides act as effective inhibitors of the folding of the protease which do not create resistance.

q-bio.BM↗

arXiv2004

Design of a folding inhibitor of the HIV-1 Protease

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 strongly interacting, highly conserved amino acids) which have evolved over myriads of generations to recognize and strongly attract each other so as to make the protein fold fast, we suggest a novel type of HIV-1-PR inhibitors which interfere with the folding of the protein: short peptides displaying the same amino acid sequence of that of LES. Theoretical and experimental evidence for the specificity and efficiency of such inhibitors are presented.

q-bio.BM↗

arXiv2004

Thermodynamics of beta-amyloid fibril formation

Amyloid fibers are aggregates of proteins. They are built out of a peptide called $β$--amyloid (A$β$) containing between 41 and 43 residues, produced by the action of an enzyme which cleaves a much larger protein known as the Amyloid Precursor Protein (APP). X-ray diffraction experiments have shown that these fibrils are rich in $β$--structures, whereas the shape of the peptide displays an $α$--helix structure within the APP in its biologically active conformation. A realistic model of fibril formation is developed based on the seventeen residues A$β$12--28 amyloid peptide, which has been shown to form fibrils structurally similar to those of the whole A$β$ peptide. With the help of physical arguments and in keeping with experimental findings, the A$β$12--28 monomer is assumed to be in four possible states (i.e., native helix conformation, $β$--hairpin, globular low--energy state and unfolded state). Making use of these monomeric states, oligomers (dimers, tertramers and octamers) were constructed. With the help of short, detailed Molecular Dynamics (MD) calculations of the three monomers and of a variety of oligomers, energies for these structures were obtained. Making use of these results within the framework of a simple yet realistic model to describe the entropic terms associated with the variety of amyloid conformations, a phase diagram can be calculated of the whole many--body system, leading to a thermodynamical picture in overall agreement with the experimental findings. In particular, the existence of micellar metastable states seem to be a key issue to determine the thermodynamical properties of the system.

q-bio.BM↗

arXiv2003

Understanding the determinants of stability and folding of small globular proteins from their energetics

The results of minimal model calculations suggest that the stability and the kinetic accessibility of the native state of small globular proteins are controlled by few "hot" sites. By mean of molecular dynamics simulations around the native conformation, which simulate the protein and the surrounding solvent at full--atom level, we generate an energetic map of the equilibrium state of the protein and simplify it with an Eigenvalue decomposition. The components of the Eigenvector associated with the lowest Eigenvalue indicate which are the "hot" sites responsible for the stability and for the fast folding of the protein. Comparison of these predictions with the results of mutatgenesis experiments, performed for five small proteins, provide an excellent agreement.

cond-mat.soft↗