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Author: Skolnick, Jeffrey × End date: 1997 × Start date: 1990 × search.filters.applied.f.isOrgUnitOfPublicationTitle: College of Sciences × Type: Text ×

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Now showing 1 - 10 of 16
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Determinants of secondary structure of polypeptide chains: Interplay between short range and burial interactions

1997-07-15 , Kolinski, Andrzej , Skolnick, Jeffrey

The effect of tertiary interactions on the observed secondary structure found in the native conformation of globular proteins was examined in the context of a reduced protein model. Short-range interactions are controlled by knowledge based statistical potentials that reflect local conformational regularities seen in a database of three-dimensional protein structures. Long-range interactions are approximated by mean field, single residue based, centrosymmetric hydrophobic burial potentials. Even when pairwise specific long-range interactions are ignored, the inclusion of such burial preferences noticeably modifies the equilibrium chain conformations, and the observed secondary structure is closer to that seen in the folded state. For a test set of 10 proteins (belonging to various structural classes), the accuracy of secondary structure prediction is about 66% and increases by 9% with respect to a related model based on short-range interactions alone [Kolinski et al., J. Chem. Phys. 103, 4312 (1995)]. The increased accuracy is due to the interplay between the short-range conformational propensities and the burial and compactness requirements built into the present model. While the absolute level of accuracy assessed on a per residue basis is comparable to more standard techniques, in contrast to these approaches, the conformation of the chain now has a better defined geometric context. For example, the assumed spherical domain protein model that simulates the segregation of residues between the hydrophobic core and the hydrophilic surface allows for the prediction of surface loops/turns where the polypeptide chain changes its direction. The implications of having such self-consistent secondary structure predictions for the prediction of protein tertiary structure are briefly discussed.

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

1995-10 , Milik, Mariusz , Skolnick, Jeffrey

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.

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Spontaneous Translocation of a Polymer across a Curved Membrane

1995-03-13 , Baumgärtner, Artur , Skolnick, Jeffrey

The translocation of a hydrophobic polymer across a curved bilayer membrane has been studied using Monte Carlo methods. It is found that for curved membranes the polymer crosses spontaneously and almost irreversibly from the side of lower curvature to the side of higher curvature. This phenomenon can be understood based upon the curvature-induced difference of lipid fluctuations between the two halves of the bilayer. The difference of fluctuations drives the polymer across the bilayer in order to maximize the conformational entropy of the polymer.

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A general method for the prediction of the three dimensional structure and folding pathway of globular proteins: Application to designed helical proteins

1993-05-01 , Kolinski, Andrzej , Godzik, Adam , Skolnick, Jeffrey

Starting from amino acid sequence alone, a general approach for simulating folding into the molten globule or rigid, native state depending on sequence is described. In particular, the 3D folds of two simple designed proteins have been predicted using a Monte Carlo folding algorithm. The model employs a very flexible hybrid lattice representation of the protein conformation, and fast lattice dynamics. A full rotamer library for side group conformations, and potentials of mean force of short and long range interactions have been extracted from the statistics of a high resolution set of nonhomologous, 3D structures of globular proteins. The simulated folding process starts from an arbitrary random conformation and relatively rapidly assembles a well defined four helix bundle. The very cooperative folding of the model systems is facilitated by the proper definition of the model protein hydrogen bond network, and multibody interactions of the side groups. The two sequences studied exhibit very different behavior. The first one, in excellent agreement with experiment, folds to a thermodynamically very stable four helix bundle that has all the properties postulated for the molten globule state. The second protein, having a more heterogeneous sequence, at lower temperature undergoes a transition from the molten globule state to the unique native state exhibiting a fixed pattern of side group packing. This marks the first time that the ability to predict a molten globule or a unique native state from sequence alone has been achieved. The implications for the general solution of the protein folding problem are briefly discussed.

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A hierarchical approach to the prediction of the quaternary structure of GCN4 and its mutants

1996 , Vieth, Michal , Kolinski, Andrzej , Brooks, C. L., III , Skolnick, Jeffrey

A hierarchical approach to protein folding is employed to examine the folding pathway and predict the quaternary structure of the GCN4 leucine zipper. Structures comparable in quality to experiment have been predicted. In addition, the equilibrium between dimers, trimers and tetramers of a number of GCN4 mutants has been examined. In five out of eight cases, the simulation results are in accordance with the experimental studies of Harbury, et al.

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A reduced model of short range interactions in polypeptide chains

1995-09-08 , Kolinski, Andrzej , Milik, Mariusz , Rycombel, Jakub , Skolnick, Jeffrey

A simple model of short range interactions is proposed for a reduced lattice representation of polypeptide conformation. The potential is derived on the basis of statistical regularities seen in the known crystal structures of globular proteins. This potential accounts for the generic stiffness of polypeptides, the correlation between peptide bond plates, and the sequence dependent correlations between consecutive segments of the C-trace. This model is used for simulation of the equilibrium and dynamic properties of polypeptides in the denatured state. It is shown that the proposed factorization of the local conformational propensities reproduces secondary structure tendencies encoded in the protein sequence. Possible applications for modeling of protein folding are briefly discussed.

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An object oriented environment for artificial evolution of protein sequences: The example of rational design of transmembrane sequences

1995 , Milik, Mariusz , Skolnick, Jeffrey

A system is presented for generating peptide sequences with desirable properties, using combination of neural network and artificial evolution. The process is illustrated by an example of a practical problem of generating artificial transbilayer peptides. The peptides generated in the process of artificial evolution have the physico-chemical properties of transmembrane peptides, and forms stable transmembrane structures in testing Monte Carlo simulations. The artificial evolution system is designed to emulate natural evolution; therefore it is of both practical and theoretical interest, both in terms of rational design of protein sequences and modeling of natural evolution of proteins.

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Computer design of idealized β-motifs

1995-12-15 , Kolinski, Andrzej , Galazka, Wojciech , Skolnick, Jeffrey

A lattice model of protein conformation and dynamics is used to explore the requirements for the de novo folding from an arbitrary random coil state of idealized models of four and six-member β-barrels. A number of possible conjectures for the factors giving rise to the structural uniqueness of globular proteins are examined. These include the relative role of generic hydrophilic/ hydrophobic amino acid patterns, the relative importance of the specific identity of the hydrophobic amino acids that form the core of the protein and the possible role played by polar groups in destabilizing alternative, misfolded conformations. These studies may also provide some insights into the relative importance of short range interactions, cooperative hydrogen bonding and tertiary interactions in determining the uniqueness of the native state, as well as the cooperativity of the folding process. Thus, these simulations may provide guidelines for the early stages of the protein design process. Possible applications to the general protein folding problem are also briefly discussed.

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A simple technique to estimate partition functions and equilibrium constants from Monte Carlo simulations

1995-04-15 , Vieth, Michal , Kolinski, Andrzej , Skolnick, Jeffrey

A combined Monte Carlo (MC) simulation-statistical mechanical treatment is proposed to calculate the internal partition function and equilibrium constant. The method has been applied to a number of one and multidimensional analytical functions. When sampling is incomplete, various factorization approximations for estimating the partition function are discussed. The resulting errors are smaller when the ratios of the partition functions are calculated (as in the determination of equilibrium constants) as opposed to the partition function itself.

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Computer simulation of the folding of coiled coils

1994-02-01 , Rey, Antonio , Skolnick, Jeffrey

A simple model capable of providing possible folding pathways of two stranded, coiled coil peptides is described and simulated using an off-lattice dynamic Monte Carlo algorithm. Short sequences of very regular repetitive blocks of amino acids are studied. The regularity of the sequence is enhanced by a simplified interaction scale between pairs of residues. Following the transition from two isolated chains in a random conformation to the folded dimeric structure, the main features capable of obtaining a parallel, in-register, unique conformation, are examined. These include the geometrical representation of the model, the cooperative development of secondary and tertiary structures, and the role of tertiary interactions stabilizing the coiled coil geometry. The influence of introducing disulfide bridges in certain locations of the sequence is also discussed.

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