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Author: Kolinski, Andrzej × Author: Skolnick, Jeffrey × End date: 1993 × Start date: 1991 × Item Type: Publication × search.filters.applied.f.isOrgUnitOfPublicationTitle: School of Biological Sciences ×

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Now showing 1 - 6 of 6
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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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Effect of double bonds on the dynamics of hydrocarbon chains

1992-07-15 , Rey, Antonio , Kolinski, Andrzej , Levine, Yehudi K. , Skolnick, Jeffrey

Brownian dynamics simulations of isolated 18-carbon chains have been performed, both for saturated and unsaturated hydrocarbons. The effect of one or several (nonconjugated) double bonds on the properties of the chains is discussed in terms of both equilibrium and dynamic properties. The introduction of a cis double bond increases the relaxation rates of the unsaturated chain with respect to the saturated alkane. On the other hand, coupling effects in the torsional transitions around a trans double bond make the dynamics of this unsaturated chain very similar to the saturated one. Based on these results, the parameters and moves of a dynamic Monte Carlo algorithm are tuned to reproduce the observed behavior, providing an efficient method for the study of more complicated systems.

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A lattice dynamics study of a Langmuir monolayer of monounsaturated fatty acids

1993-05-01 , Levine, Yehudi K. , Kolinski, Andrzej , Skolnick, Jeffrey

A Monte Carlo dynamics (MCD) scheme has been applied in a study of the effects of unsaturated double bonds on the internal conformational dynamics and orientational order of hydrocarbon chains arranged in a monolayer on the surface of an impenetrable interface. The MCD algorithm makes use of the high coordination {2 1 0} lattice for the representation of both sp³ and sp² valence states of the carbon atoms. The chain dynamics are considered to arise from a superposition of local conformational rearrangements. The simulations reproduced the principal features of the experimentally observed order parameter profiles of the C–H bonds on taking into account the intramolecular conformational energy of the molecules and excluded volume effects. The results show that the introduction of a rigid, planar, unsaturated segment enhances the orientational order in the monolayer. The extent of the enhancement is larger for the trans unsaturated chains than for the cis unsaturated ones. The increase in orientational order is accompanied by a marked increase in the effective rotational correlation times, indicating that the unsaturated segments undergo slow and restricted motion. In addition, the C–H bonds of the saturated chain segment between the cis double bond and the headgroup of the chain undergo slower motions than the corresponding vectors in the saturated and trans unsaturated chains. This arises from the anchoring of the headgroup at the impenetrable monolayer interface.

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Monte Carlo dynamics study of motions in cis-unsaturated hydrocarbon chains

1991-09-01 , Levine, Yehudi K. , Skolnick, Jeffrey , Kolinski, Andrzej

A Monte Carlo dynamics study of the motions of hydrocarbon chains containing cis double bonds is presented. The simulations utilize the high-coordination {2 1 0} lattice for the simultaneous representation of the tetrahedrally bonded carbon atoms and the planar unsaturated segment. Results on single chains undergoing free motion in space and tethered to an impenetrable planar interface are reported. The introduction of a cis double bond into a hydrocarbon chain induces a slowdown in the dynamics. The simulations show this to be a universal result independent of the representation of the chain on the lattice. In contrast, polyunsaturated chains are found to be more mobile than saturated ones.

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Discretized model of proteins. I. Monte Carlo study of cooperativity in homopolypeptides

1992-12-15 , Kolinski, Andrzej , Skolnick, Jeffrey

A discretized model of globular proteins is employed in a Monte Carlo study of the helix-coil transition of polyalanine and the collapse transition of polyvaline. The present lattice realization permits real protein crystal structures to be represented at the level of 1 A resolution. Furthermore, the Monte Carlo dynamic scheme is capable of moving elements of assembled secondary and supersecondary structure. The potentials of mean force for the interactions are constructed from the statistics of a set of high resolution x-ray structures of nonhomologous proteins. The cooperativity of formation of ordered structures is found to be larger when the major contributions to the conformational energy of the low temperature states come from hydrogen bonds and short range conformational propensities. The secondary structure seen in the folded state is the result of an interplay between the short and long range interactions. Compactness itself, driven by long range, nonspecific interactions, seems to be insufficient to generate any appreciable secondary structure. A detailed examination of the dynamics of highly helical model proteins demonstrates that all elements of secondary structure are mobile in the present algorithm, and thus the folding pathways do not depend on the use of a lattice approximation. Possible applications of the present model to the prediction of protein 3D structures are briefly discussed.

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Static and dynamic properties of a new lattice model of polypeptide chains

1991-03-01 , Kolinski, Andrzej , Milik, Mariusz , Skolnick, Jeffrey

The equilibrium and dynamic properties of a new lattice model of proteins are explored in the athermal limit. In this model, consecutive -carbons of the model polypeptide are connected by vectors of the type (±2,±1,0). In all cases, the chains have a finite backbone thickness which is close to that present in real proteins. Three different polypeptides are examined: polyglycine, polyalanine, and polyleucine. In the latter two cases, the side chains (whose conformations are extracted from known protein crystal structures) are included. For the equilibrium chain dimensions, with increasing side chain bulkiness, the effective chain length is smaller. The calculations suggest that these model polypeptides are in the same universality class as other polymer models. One surprising result is that although polyalanine and polyleucine have chiral sidechains, they do not induce a corresponding handedness of the main chain. For both polyleucine and polyalanine, the scaling of the self-diffusion constant and the terminal relaxation time are consistent with Rouse dynamics of excluded volume chains. Polyglycine exhibits a slightly stronger chain length dependence for these properties. This results from a finite length effect due to moderately long lived, local self-entanglements arising from the thin effective cross section of the chain backbone.

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