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Computational studies of TTR related amyloidosis: exploration of conformational space through petri net-based algorithm

Jakubowski R., Gogolińska A., Pepłowski Ł., Skrzyniarz P., Nowak W.

TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk

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2014

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Vol. 18, No 3

289--300

EN

Amyloidosis, a serious and widespread disease with a genetic background , manifests itself through the formation of dangerous fibrils in various organs. Apart from th e polluted environment and an unhealthy lifestyle, genetic factors may acceler ate this process leading in some cases to lethal damages to the body. Recently, a growing interest i n amyloidogenic protein research has been observed. Transthyretin ( TTR ) is a tetrameric protein that transports thyroid hormone thyroxine and retinol binding protein in plasma and the cerebr al fluid. Sometimes TTR breaks apart and forms fibrils. Several single point mutations, having de stabilizing impact on the TTR complex, are involved in the amyloidogenic TTR cascade. Problems with the TTR tetramer stability and conformational space characteristics of the protein have not been addressed computationally before. We present selected results of our molecular dynamics ( MD , ∼ 2000ns) and steered MD simulations ( SMD ) of three variants of TTR : Wild Type ( WT ), V 30 M and L 55 P . SMD has been used to enforce the dissociation of TTR . Conformational spaces of WT TTR and its amyloidogenic variants have been investigated using a novel “ One Place One Conformation ” ( OPOC ) algorithm based on a graph technique called Petri net ( PN ) formalism. While the PN approach alone does not permit a direct identification of protein regions wi th reduced stability, it gives quite a useful tool for an effective compari son of complex protein energy landscapes explored during classical and/or SMD steered molecular dynamics simulations.

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Limitation of conformational space for proteins -- early stage folding simulation of human alpha and beta hemoglobin chains

Bryliński M., Jurkowski W., Konieczny L., Roterman I.

TASK Quarterly : scientific bulletin of Academic Computer Centre in Gdansk

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2004

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Vol. 8, No 3

413-422

EN

The starting structure of ab initio protein structure prediction methods is problematic as the energy minimization procedure stops searching for an optimal structure of the function's local minimum. The method presented in the paper helps to find the starting structure. Although it is based on the known native protein structure, it seems to deliver a key to the formation of a common universal starting structure. The limited conformational sub-space, defined on the basis of a geometrical model of the polypeptide backbone with the side chain-side chain interaction excluded, seems to deliver the original structure of the polypeptide, which is modified step by step as the role of the side chain interactions increases during the energy minimization procedure. Here, the method is applied to human hemoglobin chains alpha and ß to test the applicability of the method to proteins with a high content of helical forms and lacking disulphide bonds.

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Molecular dynamics of RNA structural motif. Temperature enhanced sampling of the conformational space

Kuliński T., Kulińska K.

Computational Methods in Science and Technology

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2002

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Vol. 8, nr 2

37--45

EN

Temperature Enhanced Molecular Dynamics (TEMD) simulations were applied for the sampling of the conformational space of the RNA structural motif. During MD experiments run in explicit water and ions we observed at the atomic level the switching of the RNA tetraloop structures from the unusual conformations found in the crystal form to the conformation characteristic for the f r e e molecule in the solution. TEMD simulations prove to be useful for the exploration of the possible conformational switches, kinetic traps in RNA folding, the detection of the barriers on folding energy surfaces as well as reviling the role of water molecules and counter ions in the stabilization of RNA structure.

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Ab initio protein foldings - is conformational space searching enough?

Olszewski K.A.

Polish Journal of Chemistry

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1998

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Vol. 72, nr 7S

1667-1679

EN

Ab initio protein folding is a common name for protein structure prediction approaches, that explore the conformational space of a protein using a model of a protein and a simple, carefully designed, potential energy function. Attempts to predict the native state of the protein or to reproduce the folding pathway from a set of simple rules are essential for an understanding of the physico-chemical rules that govern the folding process. Noteworthy, a number of new techniques for protein structure/function prediction that widen the search space and the meaning of the potential energy function have emerged. In this paper the variety of approaches to protein structure or function prediction are discussed and classified with respect to their distribution in the general protein sequence-structure space.