A method for the prediction of surface "U"-turns and transglobular connections in small proteins.

A simple method for predicting the location of surface loops/turns that change the overall direction of the chain that is, "U" turns, and assigning the dominant secondary structure of the intervening transglobular blocks in small, single-domain globular proteins has been developed. Since the emphasis of the method is on the prediction of the major topological elements that comprise the global structure of the protein rather than on a detailed local secondary structure description, this approach is complementary to standard secondary structure prediction schemes. Consequently, it may be useful in the early stages of tertiary structure prediction when establishment of the structural class and possible folding topologies is of interest.

MONSSTER: a method for folding globular proteins with a small number of distance restraints.

The MONSSTER (MOdeling of New Structures from Secondary and TEritary Restraints) method for folding of proteins using a small number of long-distance restraints (which can be up to seven times less than the total number of residues) and some knowledge of the secondary structure of regular fragments is described. The method employs a high-coordination lattice representation of the protein chain that incorporates a variety of potentials designed to produce protein-like behaviour. These include statistical preferences for secondary structure, side-chain burial interactions, and a hydrogen-bond potential.

High coordination lattice models of protein structure, dynamics and thermodynamics.

A high coordination lattice discretization of protein conformational space is described. The model allows discrete representation of polypeptide chains of globular proteins and small macromolecular assemblies with an accuracy comparable to the accuracy of crystallographic structures. Knowledge based force field, that consists of sequence specific short range interactions, cooperative model of hydrogen bond network and tertiary one body, two body and multibody interactions, is outlined and discussed.

Method for low resolution prediction of small protein tertiary structure.

A new method for the de novo prediction of protein structures at low resolution has been developed. Starting from a multiple sequence alignment, protein secondary structure is predicted, and only those topological elements with high reliability are selected. Then, the multiple sequence alignment and the secondary structure prediction are combined to predict side chain contacts.

Simultaneous and coupled energy optimization of homologous proteins: a new tool for structure prediction.

Background: Homology-based modeling and global optimization of energy are two complementary approaches to prediction of protein structures. A combination of the two approaches is proposed in which a novel component is added to the energy and forces similarity between homologous proteins.

Results: The combination was tested for two families: pancreatic hormones and homeodomains.

On the origin of the cooperativity of protein folding: implications from model simulations.

There is considerable experimental evidence that the cooperativity of protein folding resides in the transition from the molten globule to the native state. The objective of this study is to examine whether simplified models can reproduce this cooperativity and if so, to identify its origin. In particular, the thermodynamics of the conformational transition of a previously designed sequence (A.

Predicting leucine zipper structures from sequence.

The leucine zipper structure is adopted by one family of the coiled coil proteins. Leucine zippers have a characteristic leucine repeat: Leu-X6-Leu-X6-Leu-X6-Liu (where X may be any residue). However, many sequences have the leucine repeat, but do not adopt the leucine zipper structure (we shall refer to these as non-zippers).

Evaluation of atomic level mean force potentials via inverse folding and inverse refinement of protein structures: atomic burial position and pairwise non-bonded interactions.

Two atomic level knowledge-based mean force interaction potentials (KBPs), a centrosymmetric burial position term and a long-range pairwise term, were developed. These were tested by comparing multiple configurations of three structurally unrelated proteins and were found successfully to (i) discriminate native state proteins from grossly misfolded structures in inverse folding tests, (ii) rank identify, using the KBP energy/r.m.

Folding simulations and computer redesign of protein A three-helix bundle motifs.

In solution, the B domain of protein A from Staphylococcus aureus (B domain) possesses a three-helix bundle structure. This simple motif has been previously reproduced by Kolinski and Skolnick (Proteins 18: 353-366, 1994) using a reduced representation lattice model of proteins with a statistical interaction scheme. In this paper, an improved version of the potential has been used, and the robustness of this result has been tested by folding from the random state a set of three-helix bundle proteins that are highly homologous to the B domain of protein A.

Method for predicting the state of association of discretized protein models. Application to leucine zippers.

A method that employs a transfer matrix treatment combined with Monte Carlo sampling has been used to calculate the configurational free energies of folded and unfolded states of lattice models of proteins. The method is successfully applied to study the monomer-dimer equilibria in various coiled coils. For the short coiled coils, GCN4 leucine zipper, and its fragments, Fos and Jun, very good agreement is found with experiment.

Prediction of the quaternary structure of coiled coils: GCN4 leucine zipper and its mutants.

A methodology for predicting coiled coil quaternary structure and for the dissection of the interactions responsible for the global fold is described. Application is made to the equilibrium between different oligomeric species of the wild type GCN4 leucine zipper and seven of its mutants that were studied by Harbury et al. Over the entire experimental concentration range, agreement with experiment is found in five cases, while in two other cases, agreement is found over a portion of the concentration range.

An algorithm for prediction of structural elements in small proteins.

A method for predicting the location of surface loops/turns and assigning the intervening secondary structure of the transglobular linkers in small, single domain globular proteins has been developed. Application to a set of 10 proteins of known structure indicates a high level of accuracy. The secondary structure assignment in the center of transglobular connections is correct in more than 85% of the cases.

Does a backwardly read protein sequence have a unique native state?

Amino acid sequences of native proteins are generally not palindromic. Nevertheless, the protein molecule obtained as a result of reading the sequence backwards, i.e.

Are proteins ideal mixtures of amino acids? Analysis of energy parameter sets.

Various existing derivations of the effective potentials of mean force for the two-body interactions between amino acid side chains in proteins are reviewed and compared to each other. The differences between different parameter sets can be traced to the reference state used to define the zero of energy. Depending on the reference state, the transfer free energy or other pseudo-one-body contributions can be present to various extents in two-body parameter sets.

A Monte Carlo model of fd and Pf1 coat proteins in lipid membranes.

A Monte Carlo Dynamics simulation was used to investigate the behavior of filamentous bacteriophage coat proteins in a model membrane environment. Our simulation agrees with the previous experimental observations that despite the low sequence similarity between the major coat proteins of Pf1 and fd bacteriophages, their structure in the membrane environment is very similar. These results support the hypothesis that the hydrophobic effect exerts an important influence on membrane protein structure.

Prediction of quaternary structure of coiled coils. Application to mutants of the GCN4 leucine zipper.

Using a simplified protein model, the equilibrium between different oligomeric species of the wild-type GCN4 leucine zipper and seven of its mutants have been predicted. Over the entire experimental concentration range, agreement with experiment is found in five cases, while in two cases agreement is found over a portion of the concentration range. These studies demonstrate a methodology for predicting coiled coil quaternary structure and allow for the dissection of the interactions responsible for the global fold.

Neural network system for the evaluation of side-chain packing in protein structures.

An artificial neural network system is used for pattern recognition in protein side-chain-side-chain contact maps. A back-propagation network was trained on a set of patterns which are popular in side-chain contact maps of protein structures. Several neural network architectures and different training parameters were tested to decide on the best combination for the neural network.

Flexible algorithm for direct multiple alignment of protein structures and sequences.

The recently described equivalence between the alignment of two proteins and a conformation of a lattice chain on a two-dimensional square lattice is extended to multiple alignments. The search for the optimal multiple alignment between several proteins, which is equivalent to finding the energy minimum in the conformational space of a multi-dimensional lattice chain, is studied by the Monte Carlo approach. This method, while not deterministic, and for two-dimensional problems slower than dynamic programming, can accept arbitrary scoring functions, including non-local ones, and its speed decreases slowly with increasing number of dimensions.

Prediction of the folding pathways and structure of the GCN4 leucine zipper.

A hierarchical approach is described for the prediction of the three-dimensional structure and folding pathway of the GCN4 leucine zipper. Dimer assembly is simulated by Monte Carlo dynamics. The resulting lowest energy structures undergo cooperative rearrangement of their hydrophobic core leading to side-chain fixation.

Monte Carlo simulations of protein folding. II. Application to protein A, ROP, and crambin.

The hierarchy of lattice Monte Carlo models described in the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulations of protein folding.

Monte Carlo simulations of protein folding. I. Lattice model and interaction scheme.

A new hierarchical method for the simulation of the protein folding process and the de novo prediction of protein three-dimensional structure is proposed. The reduced representation of the protein alpha-carbon backbone employs lattice discretizations of increasing geometrical resolution and a single ball representation of side chain rotamers. In particular, coarser and finer lattice backbone descriptions are used.

Prepubertal trauma and mandibular asymmetry in orthognathic surgery and orthodontic patients.

The association between radiographic evidence of mandibular asymmetry and history of prepubertal trauma was analyzed in orthognathic surgery patients and orthodontic patients. There were statistically significant associations between radiographic evidence of mandibular asymmetry and a history of prepubertal trauma in both patient groups. The results suggest that prepubertal trauma could be one etiologic factor for the development of mandibular asymmetry.

Regularities in interaction patterns of globular proteins.

The description of protein structure in the language of side chain contact maps is shown to offer many advantages over more traditional approaches. Because it focuses on side chain interactions, it aids in the discovery, study and classification of similarities between interactions defining particular protein folds and offers new insights into the rules of protein structure. For example, there is a small number of characteristic patterns of interactions between protein supersecondary structural fragments, which can be seen in various non-related proteins.

De novo and inverse folding predictions of protein structure and dynamics.

In the last two years, the use of simplified models has facilitated major progress in the globular protein folding problem, viz., the prediction of the three-dimensional (3D) structure of a globular protein from its amino acid sequence. A number of groups have addressed the inverse folding problem where one examines the compatibility of a given sequence with a given (and already determined) structure.