Biomedical subjects

M Vendruscolo

Publications and source records attributed to M Vendruscolo.

11 recordsLinked to original sources

PubMed2000

Can a pairwise contact potential stabilize native protein folds against decoys obtained by threading?

We present a method to derive contact energy parameters from large sets of proteins. The basic requirement on which our method is based is that for each protein in the database the native contact map has lower energy than all its decoy conformations that are obtained by threading. Only when this condition is satisfied one can use the proposed energy function for fold identification. Such a set of parameters can be found (by perceptron learning) if Mp, the number of proteins in the database, is not too large. Other aspects that influence the existence of such a solution are the exact definition of contact and the value of the critical distance Rc, below which two residues are considered to be in contact. Another important novel feature of our approach is its ability to determine whether an energy function of some suitable proposed form can or cannot be parameterized in a way that satisfies our basic requirement. As a demonstration of this, we determine the region in the (Rc, Mp) plane in which the problem is solvable, i.e., we can find a set of contact parameters that stabilize simultaneously all the native conformations. We show that for large enough databases the contact approximation to the energy cannot stabilize all the native folds even against the decoys obtained by gapless threading.

Algorithms↗

PubMed2000

Protein folding using contact maps.

We discuss the problem of representations of protein structure and give the definition of contact maps. We present a method to obtain a three-dimensional polypeptide conformation from a contact map. We also explain how to deal with the case of nonphysical contact maps. We describe a stochastic method to perform dynamics in contact map space. We explain how the motion is restricted to physical regions of the space. First, we introduce the exact free energy of a contact map and discuss two simple approximations to it. Second, we present a method to derive energy parameters based on perception learning. We prove in an extensive number of situations that the pairwise contact approximation both when alone and when supplemented with a hydrophobic term is unsuitable for stabilizing proteins' native states.

Aprotinin↗

PubMed1999

Folding Lennard-Jones proteins by a contact potential.

We studied the possibility to approximate a Lennard-Jones interaction by a pairwise contact potential. First we used a Lennard-Jones potential to design off-lattice, protein-like heteropolymer sequences, whose lowest energy (native) conformations were then identified by molecular dynamics. Then we turned to investigate whether one can find a pairwise contact potential, whose ground states are the contact maps associated with these native conformations. We show that such a requirement cannot be satisfied exactly, i.e., no such contact parameters exist. Nevertheless, we found that one can find contact energy parameters for which an energy minimization procedure, acting in the space of contact maps, yields maps whose corresponding structures are close to the native ones. Finally, we show that when these structures are used as the initial point of a molecular dynamics energy minimization process, the correct native folds are recovered with high probability.

Drug Design↗

PubMed1999

Neutral evolution of model proteins: diffusion in sequence space and overdispersion.

We stimulate the evolution of model protein sequences subject to mutations. A mutation is considered neutral if it conserves (1) the structure of the ground state, (2) its thermodynamic stability and (3) its kinetic accessibility. All other mutations are considered lethal and are rejected. We adopt a lattice model, amenable to a reliable solution of the protein folding problem. We prove the existence of extended neutral networks in sequence space-sequences can evolve until their similarity with the starting point is almost the same as for random sequences. Furthermore, we find that the rate of neutral mutations has a broad distribution in sequence space. Due to this fact, the substitution process is overdispersed (the ratio between variance and mean is larger than 1). This result is in contrast with the simplest model of neutral evolution, which assumes a Poisson process for substitutions, and in qualitative agreement with the biological data.

Animals↗

PubMed1998

Efficient dynamics in the space of contact maps.

BACKGROUND: Two problems are of major importance in protein fold prediction: how to generate plausible conformations, and how to choose an energy function to identify the native state. Contact maps are a simple representation of protein structure and offer a promising framework to address these two issues. RESULTS: In this work we develop Monte Carlo dynamics in contact map space. The procedure is divided into four steps: non-local dynamics, in which large-scale "cluster" moves are performed (clusters are in approximate correspondence with secondary structure elements); local dynamics, in which secondary structure location is optimized; reconstruction, in which the physicality of the contact map is restored; and refinement, which consists of a further Monte Carlo energy minimization in real space. We demonstrate that such a dynamical procedure is effective in producing uncorrelated low-energy states. CONCLUSIONS: The procedure introduced in this paper very effectively generates a representative ensemble of conformations. We are able to show that existing sets of pairwise contact energy parameters are not suitable to single out the native state within this ensemble. The remaining outstanding issue in protein folding is to find an energy function that can discriminate the native state from decoys.

Models, Chemical↗

PubMed1997

Recovery of protein structure from contact maps.

BACKGROUND: Prediction of a protein's structure from its amino acid sequence is a key issue in molecular biology. While dynamics, performed in the space of two-dimensional contact maps, eases the necessary conformational search, it may also lead to maps that do not correspond to any real three-dimensional structure. To remedy this, an efficient procedure is needed to reconstruct three-dimensional conformations from their contact maps. RESULTS: We present an efficient algorithm to recover the three-dimensional structure of a protein from its contact map representation. We show that when a physically realizable map is used as target, our method generates a structure whose contact map is essentially similar to the target. furthermore, the reconstructed and original structures are similar up to the resolution of the contact map representation. Next, we use nonphysical target maps, obtained by corrupting a physical one; in this case, our method essentially recovers the underlying physical map and structure. Hence, our algorithm will help to fold proteins, using dynamics in the space of contact maps. Finally, we investigate the manner in which the quality of the recovered structure degrades when the number of contacts is reduced. CONCLUSIONS: The procedure is capable of assigning quickly and reliably a three-dimensional structure to a given contact map. It is well suited for use in parallel with dynamics in contact map space to project a contact map onto its closest physically allowed structural counterpart.

Algorithms↗

PubMed1996