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      Knotted proteins: A tangled tale of Structural Biology

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          Abstract

          Knotted proteins have their native structures arranged in the form of an open knot. In the last ten years researchers have been making significant efforts to reveal their folding mechanism and understand which functional advantage(s) knots convey to their carriers. Molecular simulations have been playing a fundamental role in this endeavor, and early computational predictions about the knotting mechanism have just been confirmed in wet lab experiments. Here we review a collection of simulation results that allow outlining the current status of the field of knotted proteins, and discuss directions for future research.

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          Most cited references114

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          Molecular chaperones in protein folding and proteostasis.

          Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
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            The protein-folding problem, 50 years on.

            The protein-folding problem was first posed about one half-century ago. The term refers to three broad questions: (i) What is the physical code by which an amino acid sequence dictates a protein's native structure? (ii) How can proteins fold so fast? (iii) Can we devise a computer algorithm to predict protein structures from their sequences? We review progress on these problems. In a few cases, computer simulations of the physical forces in chemically detailed models have now achieved the accurate folding of small proteins. We have learned that proteins fold rapidly because random thermal motions cause conformational changes leading energetically downhill toward the native structure, a principle that is captured in funnel-shaped energy landscapes. And thanks in part to the large Protein Data Bank of known structures, predicting protein structures is now far more successful than was thought possible in the early days. What began as three questions of basic science one half-century ago has now grown into the full-fledged research field of protein physical science.
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              Efficient, multiple-range random walk algorithm to calculate the density of states.

              We present a new Monte Carlo algorithm that produces results of high accuracy with reduced simulational effort. Independent random walks are performed (concurrently or serially) in different, restricted ranges of energy, and the resultant density of states is modified continuously to produce locally flat histograms. This method permits us to directly access the free energy and entropy, is independent of temperature, and is efficient for the study of both 1st order and 2nd order phase transitions. It should also be useful for the study of complex systems with a rough energy landscape.
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                Author and article information

                Contributors
                Journal
                Comput Struct Biotechnol J
                Comput Struct Biotechnol J
                Computational and Structural Biotechnology Journal
                Research Network of Computational and Structural Biotechnology
                2001-0370
                19 August 2015
                2015
                19 August 2015
                : 13
                : 459-468
                Affiliations
                Departament of Physics and BioISI—Biosystems & Integrative Sciences Institute, Faculdade de Ciências, Universidade de Lisboa, Campo Grande, Lisboa, Portugal
                Article
                S2001-0370(15)00038-0
                10.1016/j.csbj.2015.08.003
                4556803
                26380658
                bca92b96-e43f-4a58-be66-1d876c6c8164
                © 2015 Faísca. Published by Elsevier B.V. on behalf of the Research Network of Computational and Structural Biotechnology.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 28 May 2015
                : 31 July 2015
                : 7 August 2015
                Categories
                Mini-Review

                knotted proteins,protein folding,molecular simulations,kinetic stability,protein evolution

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