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1
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Protein modeling and structure prediction with a reduced representation.

100%
Kolinski A.
Acta Biochimica Polonica
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2004
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vol. 51
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issue 2
349-371
EN
Protein modeling could be done on various levels of structural details, from simplified lattice or continuous representations, through high resolution reduced models, employing the united atom representation, to all-atom models of the molecular mechanics. Here I describe a new high resolution reduced model, its force field and applications in the structural proteomics. The model uses a lattice representation with 800 possible orientations of the virtual alpha carbon-alpha carbon bonds. The sampling scheme of the conformational space employs the Replica Exchange Monte Carlo method. Knowledge-based potentials of the force field include: generic protein-like conformational biases, statistical potentials for the short-range conformational propensities, a model of the main chain hydrogen bonds and context-dependent statistical potentials describing the side group interactions. The model is more accurate than the previously designed lattice models and in many applications it is complementary and competitive in respect to the all-atom techniques. The test applications include: the ab initio structure prediction, multitemplate comparative modeling and structure prediction based on sparse experimental data. Especially, the new approach to comparative modeling could be a valuable tool of the structural proteomics. It is shown that the new approach goes beyond the range of applicability of the traditional methods of the protein comparative modeling.
2
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Computational study of binding of epothilone A to β-tubulin

63%
Kamel K., Kolinski A.
Acta Biochimica Polonica
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2011
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vol. 58
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issue 2
255-260
EN
Understanding the interactions of epothilones with β-tubulin is crucial for computer aided rational design of macrocyclic drugs based on epothilones and epothilone derivatives. Despite numerous structure-activity relationship investigations we still lack substantial knowledge about the binding mode of epothilones and their derivatives to β-tubulin. In this work, we reevaluated the electron crystallography structure of epothilone A/β-tubulin complex (PDB entry 1TVK) and proposed an alternative binding mode of epothilone A to β-tubulin that explains more experimental facts.
3
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Assessment of the free binding energy of 1,25-dihydroxyvitamin D3 and its analogs with the human VDR receptor model

63%
Kamel K., Kolinski A.
Acta Biochimica Polonica
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2012
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vol. 59
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issue 4
653-660
EN
1,25-dihydroxyvitamin D3 has quite significant anticancer properties, but its strong calcemic effect in principle excludes it as a potential anticancer drug. Currently, a lot of effort is being devoted to develop potent anticancer analogs of 1,25-dihydroxyvitamin D3 that would not induce hypercalcemia during therapy. In this work, the free binding energy of the VDR receptor with 1,25-dihydroxyvitamin D3 and its three potent analogs (EB 1089, KH 1060 and RO 25-9022) is calculated and compared with each other. With this approach, we could estimate the relative binding affinity of the most potent analog, RO 25-9022, and also revealed a quite distinct mechanism of its interaction with VDR.
4
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Computer simulations of protein folding with a small number of distance restraints.

51%
Sikorski A., Kolinski A., Skolnick J.
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vol. 49
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issue 3
683-692
EN
A high coordination lattice model was used to represent the protein chain. Lattice points correspond to amino-acid side groups. A complicated force field was designed in order to reproduce a protein-like behavior of the chain. Long-distance tertiary restraints were also introduced into the model. The Replica Exchange Monte Carlo method was applied to find the lowest energy states of the folded chain and to solve the problem of multiple minima. In this method, a set of replicas of the model chain was simulated independently in different temperatures with the exchanges of replicas allowed. The model chains, which consisted of up to 100 residues, were folded to structures whose root-mean-square deviation (RMSD) from their native state was between 2.5 and 5 Å. Introduction of restrain based on the positions of the backbone hydrogen atoms led to an improvement in the number of successful simulation runs. A small improvement (about 0.5 Å) was also achieved in the RMSD of the folds. The proposed method can be used for the refinement of structures determined experimentally from NMR data.
5
Content available remote

TRACER. A new approach to comparative modeling that combines threading with free-space conformational sampling

51%
Trojanowski S., Rutkowska A., Kolinski A.
Acta Biochimica Polonica
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2010
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vol. 57
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issue 1
125-133
EN
A new approach to comparative modeling of proteins, TRACER, is described and benchmarked against classical modeling procedures. The new method unifies true three-dimensional threading with coarse-grained sampling of query protein conformational space. The initial sequence alignment of a query protein with a template is not required, although a template needs to be somehow identified. The template is used as a multi-featured fuzzy three-dimensional scaffold. The conformational search for the query protein is guided by intrinsic force field of the coarse-grained modeling engine CABS and by compatibility with the template scaffold. During Replica Exchange Monte Carlo simulations the model chain representing the query protein finds the best possible structural alignment with the template chain, that also optimizes the intra-protein interactions as approximated by the knowledge based force field of CABS. The benchmark done for a representative set of query/template pairs of various degrees of sequence similarity showed that the new method allows meaningful comparative modeling also for the region of marginal, or non-existing, sequence similarity. Thus, the new approach significantly extends the applicability of comparative modeling.
6
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Denatured proteins and early folding intermediates simulated in a reduced conformational space

45%
Kmiecik S., Kurcinski M., Rutkowska A., Gront D., Kolinski A.
Acta Biochimica Polonica
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2006
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vol. 53
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issue 1
131-144
EN
Conformations of globular proteins in the denatured state were studied using a high-resolution lattice model of proteins and Monte Carlo dynamics. The model assumes a united-atom and high-coordination lattice representation of the polypeptide conformational space. The force field of the model mimics the short-range protein-like conformational stiffness, hydrophobic interactions of the side chains and the main-chain hydrogen bonds. Two types of approximations for the short-range interactions were compared: simple statistical potentials and knowledge-based protein-specific potentials derived from the sequence-structure compatibility of short fragments of protein chains. Model proteins in the denatured state are relatively compact, although the majority of the sampled conformations are globally different from the native fold. At the same time short protein fragments are mostly native-like. Thus, the denatured state of the model proteins has several features of the molten globule state observed experimentally. Statistical potentials induce native-like conformational propensities in the denatured state, especially for the fragments located in the core of folded proteins. Knowledge-based protein-specific potentials increase only slightly the level of similarity to the native conformations, in spite of their qualitatively higher specificity in the native structures. For a few cases, where fairly accurate experimental data exist, the simulation results are in semiquantitative agreement with the physical picture revealed by the experiments. This shows that the model studied in this work could be used efficiently in computational studies of protein dynamics in the denatured state, and consequently for studies of protein folding pathways, i.e. not only for the modeling of folded structures, as it was shown in previous studies. The results of the present studies also provide a new insight into the explanation of the Levinthal's paradox.
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