Hiking in the energy landscape in sequence space: a bumpy road to good folders

With the help of a simple 20 letters, lattice model of heteropolymers, we investigate the energy landscape in the space of designed good-folder sequences. Low-energy sequences form clusters, interconnected via neutral networks, in the space of sequences. Residues which play a key role in the foldability of the chain and in the stability of the native state are highly conserved, even among the chains belonging to different clusters. If, according to the interaction matrix, some strong attractive interactions are almost degenerate (i.e. they can be realized by more than one type of aminoacid contacts) sequence clusters group into a few super-clusters. Sequences belonging to different super-clusters are dissimilar, displaying very small ($\approx 10$) similarity, and residues in key-sites are, as a rule, not conserved. Similar behavior is observed in the analysis of real protein sequences.Comment: 17 pages 5 figures Corrected typos added auxiliary informatio

Simple models of protein folding and of non--conventional drug design

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 a protein whose sequence is known. Using insight obtained from simple model simulations of the folding of proteins, in particular of the fact that this phenomenon is essentially controlled by conserved (native) contacts among (few) strongly interacting ("hot"), as a rule hydrophobic, amino acids, which also stabilize local elementary structures (LES, hidden, incipient secondary structures like $\alpha$--helices and $\beta$--sheets) formed early in the folding process and leading to the postcritical folding nucleus (i.e., the minimum set of native contacts which bring the system pass beyond the highest free--energy barrier found in the whole folding process) it is possible to work out a succesful strategy for reading the native structure of designed proteins from the knowledge of only their amino acid sequence and of the contact energies among the amino acids. Because LES have undergone millions of years of evolution to selectively dock to their complementary structures, small peptides made out of the same amino acids as the LES are expected to selectively attach to the newly expressed (unfolded) protein and inhibit its folding, or to the native (fluctuating) native conformation and denaturate it. These peptides, or their mimetic molecules, can thus be used as effective non--conventional drugs to those already existing (and directed at neutralizing the active site of enzymes), displaying the advantage of not suffering from the uprise of resistance

Structural role of hydrophobic core in proteins-selected examples

This paper discusses the sequence/structure relation. The core question concerns the degree to which similar sequences produce similar structures and vice versa. A mechanism by which similar sequences may result in dissimilar structures is proposed, based on the Fuzzy Oil Drop (FOD) model in which structural similarity is estimated by analyzing the protein’s hydrophobic core. We show that local changes in amino acid sequences, in addition to producing local structural alterations at the substitution site, may also change the shape of the hydrophobic core, significantly affecting the overall tertiary conformation of the protein. Our analysis focuses on four sets of proteins: 1) Pair of designer proteins with specially prepared sequences; 2) Pair of natural proteins modified (mutated) to converge to a point of high-level sequence identity while retaining their respective wild-type tertiary folds; 3) Pair of natural proteins with common ancestry but with differing structures and biological profiles shaped by divergent evolution; and 4) Pair of natural proteins of high structural similarity with no sequence similarity and different biological function