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Insights into Gene Expression and Packaging from Computer Simulations.

ABSTRACT: Within the nucleus of each cell lies DNA - an unfathomably long, twisted, and intricately coiled molecule - segments of which make up the genes that provide the instructions that a cell needs to operate. As we near the 60(th) anniversary of the discovery of the DNA double helix, crucial questions remain about how the physical arrangement of the DNA in cells affects how genes work. For example, how a cell stores the genetic information inside the nucleus is complicated by the necessity of maintaining accessibility to DNA for genetic processing. In order to gain insight into the roles played by various proteins in reading and compacting the genome, we have developed new methodologies to simulate the dynamic, three-dimensional structures of long, fluctuating, protein-decorated strands of DNA. Our a priori approach to the problem allows us to determine the effects of individual proteins and their chemical modifications on overall DNA structure and function. Here we present our recent treatment of the communication between regulatory proteins attached to precisely constructed stretches of chromatin. Our simulations account for the enhancement in communication detected experimentally on chromatin compared to protein-free DNA of the same chain length as well as the critical roles played by the cationic 'tails' of the histone proteins in this signaling. The states of chromatin captured in the simulations offer new insights into the ways that the DNA, histones, and regulatory proteins contribute to long-range communication along the genome.

SUBMITTER: Olson WK

PROVIDER: S-EPMC3489483 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe tumour suppressor protein p53 protein has a core domain that binds DNA and is the site for most oncogenic mutations. This domain is quite unstable compared to its homologs p63 and p73. Two key residues in the core domain of p53 (Tyr236, Thr253), have been mutated in-silico, to their equivalent residues in p63 (Phe238 and Ile255) and p73 (Phe238 and Ile255), with subsequent increase in stability of p53. Computational studies have been performed to examine the basis of instability in p53.ResultsMolecular dynamics simulations suggest that mutations in p53 lead to increased conformational sampling of the phase space which stabilizes the system entropically. In contrast, reverse mutations, where p63 and p73 were mutated by replacing the Phe238 and Ile255 by Tyr and Thr respectively (as in p53), showed reduced conformational sampling although the change for p63 was much smaller than that for p73. Barriers to the rotation of sidechains containing aromatic rings at the core of the proteins were reduced several-fold when p53 was mutated; in contrast they increased when p73 was mutated and decreased by a small amount in p63. The rate of ring flipping of a Tyrosine residue at the boundary of two domains can be correlated with the change in stability, with implications for possible pathways of entry of agents that induce unfolding.ConclusionA double mutation at the core of the DNA binding domain of p53 leads to enhanced stability by increasing the softness of the protein. A change from a highly directional polar interaction of the core residues Tyr236 and Thr253 to a non-directional apolar interaction between Phe and Ile respectively may enable the system to adapt more easily and thus increase its robustness to structural perturbations, giving it increased stability. This leads to enhanced conformational sampling which in turn is associated with an increased "softness" of the protein core. However the system seems to become more rigid at the periphery. The success of this methodology in reproducing the experimental trends in the stability of p53 suggests that it has the potential to complement structural studies for rapidly estimating changes in stability upon mutations and could be an additional tool in the design of specific classes of proteins.

Project description:How do the feedbacks between tectonics, sediment transport and climate work to shape the topographic evolution of the Earth? This question has been widely addressed via numerical models constrained with thermochronological and geomorphological data at scales ranging from local to orogenic. Here we present a novel numerical model that aims at reproducing the interaction between these processes at the continental scale. For this purpose, we combine in a single computer program: 1) a thin-sheet viscous model of continental deformation; 2) a stream-power surface-transport approach; 3) flexural isostasy allowing for the formation of large sedimentary foreland basins; and 4) an orographic precipitation model that reproduces basic climatic effects such as continentality and rain shadow. We quantify the feedbacks between these processes in a synthetic scenario inspired by the India-Asia collision and the growth of the Tibetan Plateau. We identify a feedback between erosion and crustal thickening leading locally to a <50% increase in deformation rates in places where orographic precipitation is concentrated. This climatically-enhanced deformation takes place preferentially at the upwind flank of the growing plateau, specially at the corners of the indenter (syntaxes). We hypothesize that this may provide clues for better understanding the mechanisms underlying the intriguing tectonic aneurisms documented in the Himalayas. At the continental scale, however, the overall distribution of topographic basins and ranges seems insensitive to climatic factors, despite these do have important, sometimes counterintuitive effects on the amount of sediments trapped within the continent. The dry climatic conditions that naturally develop in the interior of the continent, for example, trigger large intra-continental sediment trapping at basins similar to the Tarim Basin because they determine its endorheic/exorheic drainage. These complex climatic-drainage-tectonic interactions make the development of steady-state topography at the continental scale unlikely.

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Insights into Gene Expression and Packaging from Computer Simulations.

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