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J Skolnick

Publications and source records attributed to J Skolnick.

At least 73 records · Page 4Linked to original sources
PubMed1996

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. Furthermore, an attempt to redesign the B domain native structure to its topological mirror image fold has been made by multiple mutations of the hydrophobic core and the turn region between helices I and II. A sieve method for scanning a large set of mutations to search for this desired property has been proposed. It has been shown that mutations of native B domain hydrophobic core do not introduce significant changes in the protein motif. Mutations in the turn region were also very conservative; nevertheless, a few mutants acquired the desired topological mirror image motif. A set of all atom models of the most probable mutant was reconstructed from the reduced models and refined using a molecular dynamics algorithm in the presence of water. The packing of all atom structures obtained corroborates the lattice model results. We conclude that the change in the handedness of the turn induced by the mutations, augmented by the repacking of hydrophobic core and the additional burial of the second helix N-cap side chain, are responsible for the predicted preferential adoption of the mirror image structure.

Computer Simulation↗
PubMed1996

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. Kolinski, W. Galazka, and J. Skolnick, J. Chem. Phys. 103: 10286-10297, 1995), which adopts a very stable Greek-key beta-barrel fold has been investigated using the entropy Monte Carlo sampling (ESMC) technique of Hao and Scheraga (M.-H. Hao and H.A. Scheraga, J. Phys. Chem. 98: 9882-9883, 1994). Here, in addition to the original potential, which includes one body and pair interactions between side chains, the force field has been supplemented by two types of multi-body potentials describing side chain interactions. These potentials facilitate the protein-like pattern of side chain packing and consequently increase the cooperativity of the folding process. Those models that include an explicit cooperative side chain packing term exhibit a well-defined all-or-none transition from a denatured, random coil state to a high-density, well-defined, nativelike low-energy state. By contrast, models lacking such a term exhibit a conformational transition that is essentially continuous. Finally, an examination of the conformations at the free-energy barrier between the native and denatured states reveals that they contain a substantial amount of native-state secondary structure, about 50% of the native contacts, and have an average root mean square radius of gyration that is about 15% larger than native.

Amino Acids↗
PubMed1996

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. a retro-protein, obviously has the same amino acid composition and the same hydrophobicity profile as the native sequence. The important questions which arise in the context of retro-proteins are: does a retro-protein fold to a well defined native-like structure as natural proteins do and, if the answer is positive, does a retro-protein fold to a structure similar to the native conformation of the original protein? In this work, the fold of retro-protein A, originated from the retro-sequence of the B domain of Staphylococcal protein A, was studied. As a result of lattice model simulations, it is conjectured that the retro-protein A also forms a three-helix bundle structure in solution. It is also predicted that the topology of the retro-protein A three-helix bundle is that of the native protein A, rather than that corresponding to the mirror image of native protein A. Secondary structure elements in the retro-protein do not exactly match their counterparts in the original protein structure; however, the amino acid side chain contract pattern of the hydrophobic core is partly conserved.

Amino Acid Sequence↗
PubMed1996

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.s.d. correlation, native from progressively less native-like (compact and dilated) structures generated via molecular dynamics sampling, providing an energy gradient sloping from partially unfolded structures towards near-native states in inverse refinement tests (iii) smooth the overall potential energy surface in the region of dilated non-native structures by countering local minima of the in vacuo molecular mechanical potential and (iv) serve as a local minimum detector during simulated temperature quenching studies. These atomic KBPs discriminated native from non-native structures with greater overall sensitivity than did either a residue-based pairwise interaction potential or an effective solvation potential based on atomic contact volume occupancy. The KBPs presented here are immediately useful as a tool for selecting "good refinement candidates' from an arbitrary collection of protein configurations and may play a role in dynamic computational protein refinement.

Flavodoxin↗
PubMed1996

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). We have found and analyzed residue pair patterns that allow one to identify correctly 90% of leucine zippers and 97% of non-zippers. Simpler analyses, based on the frequency of occurrence of residues at certain positions, specify, at most, 65% of zippers and 80-90% of non-zippers. Both short and long patterns contribute to the successful discrimination of leucine zippers from non-zippers. A number of these patterns involve hydrophobic residues that would be placed on the solvent-exposed surface of the helix, were the sequence to adopt a leucine zipper structure. Thus, an analysis of protein sequences has allowed us to improve discrimination between leucine zippers and non-zippers, and has provided some further insight into the physical factors influencing the leucine zipper structure.

Amino Acid Sequence↗
PubMed1996

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. A similar error rate is found for loops. Since more global information about the fold is provided, it is complementary to standard secondary structure prediction approaches. Consequently, it may be useful in early stages of tertiary structure prediction when establishment of the structural class and possible folding topologies is of interest.

Algorithms↗
PubMed1996

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. These simulations suggest that the degree of chain association is determined by the balance between specific side chain packing preferences and the entropy reduction associated with side chain burial in higher order multimers.

Amino Acid Substitution↗
PubMed1995

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. In agreement with the conclusion of Harbury et al., the results of the simulations indicate that the pattern of hydrophobic and hydrophilic residues alone is insufficient to define a protein's three-dimensional structure. In addition, these simulations indicate that the degree of chain association is determined by the balance between specific side-chain packing preferences and the entropy reduction associated with side-chain burial in higher-order multimers.

Computer Simulation↗
PubMed1995

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. It is, however, possible to compare various derivations directly by concentrating on the "excess" energy-a term that describes the difference between a real protein and an ideal solution of amino acids. Furthermore, the number of protein structures available for analysis allows one to check the consistency of the derivation and the errors by comparing parameters derived from various subsets of the whole database. It is shown that pair interaction preferences are very consistent throughout the database. Independently derived parameter sets have correlation coefficients on the order of 0.8, with the mean difference between equivalent entries of 0.1 kT. Also, the low-quality (low resolution, little or no refinement) structures show similar regularities. There are, however, large differences between interaction parameters derived on the basis of crystallographic structures and structures obtained by the NMR refinement. The origin of the latter difference is not yet understood.

Amino Acid Sequence↗
PubMed1995

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. The model may also be used for modeling the insertion and transport processes in protein-membrane systems. The example of fd protein was also used as a test of sensitivity of our model to temperature, thickness of the hydrocarbon phase, and simulation time. In all cases, the results were independent (over the tested range) of the particular values of the parameters.

Amino Acid Sequence↗
PubMed1995

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. The resulting network can distinguish between original (from protein structures) and randomized patterns with an accuracy of 84.5% and a Matthews' coefficient of 0.72 for the testing set. Applications of this system for protein structure evaluation and refinement are also proposed. Examples include structures obtained after the application of molecular dynamics to crystal structures, structures obtained from X-ray crystallography at various stages of refinement, structures obtained from a de novo folding algorithm and deliberately misfolded structures.

Amino Acid Sequence↗
PubMed1994

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. The coarse-grained structures are further refined using a molecular dynamics annealing protocol. This produces full atom models with a backbone root-mean-square deviation from the crystal structure of 0.81 A. Thus, we demonstrate the predictive ability of our approach to yield high resolution structures of small coiled coils from their sequence.

Amino Acid Sequence↗
PubMed1994

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. The coarser (finer) lattice represents C alpha traces of native proteins with an accuracy of 1.0 (0.7) A rms. Folding is simulated by means of very fast Monte Carlo lattice dynamics. The potential of mean force, predominantly of statistical origin, contains several novel terms that facilitate the cooperative assembly of secondary structure elements and the cooperative packing of the side chains. Particular contributions to the interaction scheme are discussed in detail. In the accompanying paper (Kolinski, A., Skolnick, J. Monte Carlo simulation of protein folding. II. Application to protein A, ROP, and crambin. Proteins 18:353-366, 1994), the method is applied to three small globular proteins.

Amino Acid Sequence↗
PubMed1994

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. I. Lattice model and interaction scheme. Proteins 18:338-352, 1994) is applied to the simulation of protein folding and the prediction of 3-dimensional structure. Using sequence information alone, three proteins have been successfully folded: the B domain of staphylococcal protein A, a 120 residue, monomeric version of ROP dimer, and crambin. Starting from a random expanded conformation, the model proteins fold along relatively well-defined folding pathways. These involve a collection of early intermediates, which are followed by the final (and rate-determining) transition from compact intermediates closely resembling the molten globule state to the native-like state. The predicted structures are rather unique, with native-like packing of the side chains. The accuracy of the predicted native conformations is better than those obtained in previous folding simulations. The best (but by no means atypical) folds of protein A have a coordinate rms of 2.25 A from the native C alpha trace, and the best coordinate rms from crambin is 3.18 A. For ROP monomer, the lowest coordinate rms from equivalent C alpha s of ROP dimer is 3.65 A. Thus, for two simple helical proteins and a small alpha/beta protein, the ability to predict protein structure from sequence has been demonstrated.

Amino Acid Sequence↗
PubMed1994

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.

Adolescent↗
PubMed1994

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. For the local scoring functions, the MC algorithm can also reproduce known exact solutions for the direct multiple alignments. As illustrated by examples, both for structure- and sequence-based alignments, direct multi-dimensional alignments are able to capture weak similarities between divergent families much better than ones built from pairwise alignments by a hierarchical approach.

Algorithms↗
PubMed1993

A method for predicting protein structure from sequence.

BACKGROUND: The ability to predict the native conformation of a globular protein from its amino-acid sequence is an important unsolved problem of molecular biology. We have previously reported a method in which reduced representations of proteins are folded on a lattice by Monte Carlo simulation, using statistically-derived potentials. When applied to sequences designed to fold into four-helix bundles, this method generated predicted conformations closely resembling the real ones. RESULTS: We now report a hierarchical approach to protein-structure prediction, in which two cycles of the above-mentioned lattice method (the second on a finer lattice) are followed by a full-atom molecular dynamics simulation. The end product of the simulations is thus a full-atom representation of the predicted structure. The application of this procedure to the 60 residue, B domain of staphylococcal protein A predicts a three-helix bundle with a backbone root mean square (rms) deviation of 2.25-3 A from the experimentally determined structure. Further application to a designed, 120 residue monomeric protein, mROP, based on the dimeric ROP protein of Escherichia coli, predicts a left turning, four-helix bundle native state. Although the ultimate assessment of the quality of this prediction awaits the experimental determination of the mROP structure, a comparison of this structure with the set of equivalent residues in the ROP dime- crystal structure indicates that they have a rms deviation of approximately 3.6-4.2 A. CONCLUSION: Thus, for a set of helical proteins that have simple native topologies, the native folds of the proteins can be predicted with reasonable accuracy from their sequences alone. Our approach suggest a direction for future work addressing the protein-folding problem.

Journal Article↗