Thu, 07 Aug 2008 22:01:03 BST CiteULike: cactus's Han http://www.citeulike.org/user/cactus/author/Han CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/cactus/article/2689148 <i>Proceedings of the National Academy of Sciences (17 April 2008), 0708708105.</i><br /><br />We develop a probabilistic method for analyzing global features of a cellular network under intrinsic statistical fluctuations, which is important when there are finite numbers of molecules. By making a self-consistent mean field approximation of splitting the variables in order to reduce the large number of degrees of freedom, which is reasonable for a not very strongly interacting network, we discovered that the underlying energy landscape of the mitogen-activated protein kinases (MAPKs) signal transduction network (with experimentally measured or inferred parameters such as chemical reaction rate coefficients in the network) is funneled toward a global minimum characterized by the nonequilibrium steady-state fixed point of the system at the end of the signal transduction process. For this system, we also show that the energy landscape is robust against intrinsic fluctuations and random perturbation to the inherent chemical reaction rates. The ratio of the slope versus the roughness of the energy landscape becomes a quantitative measure of robustness and stability of the network. Furthermore, we quantify the dissipation cost of this nonequilibrium system through entropy production, caused by the nonequilibrium flux in the system. We found that a lower dissipation cost corresponds to a more robust network. This least dissipation property might provide a design principle for robust and functional networks. Finally, we find the possibility of bistable and oscillatory-like solutions, which are important for cell fate decisions, upon perturbations. The method described here can be used in a variety of biological networks. 10.1073/pnas.0708708105 Intrinsic noise, dissipation cost, and robustness of cellular networks: The underlying energy landscape of MAPK signal transduction Saul Lapidus Bo Han Jin Wang doi:10.1073/pnas.0708708105 Proceedings of the National Academy of Sciences (17 April 2008), 0708708105. 2008-04-18T18:35:19-00:00 2008 Proceedings of the National Academy of Sciences 0708708105 cell network signal http://www.citeulike.org/user/cactus/article/2410965 <i>Proceedings of the National Academy of Sciences, Vol. 105, No. 7. (19 February 2008), pp. 2397-2402.</i><br /><br />Recent experiments claiming that Naf-BBL protein follows a global downhill folding raised an important controversy as to the folding mechanism of fast-folding proteins. Under the global downhill folding scenario, not only do proteins undergo a gradual folding, but folding events along the continuous folding pathway also could be mapped out from the equilibrium denaturation experiment. Based on the exact calculation using a free energy landscape, relaxation eigenmodes from a master equation, and Monte Carlo simulation of an extended MunozEaton model that incorporates multiscale-heterogeneous pairwise interactions between amino acids, here we show that the very nature of a two-state cooperative transition such as a bimodal distribution from an exact free energy landscape and biphasic relaxation kinetics manifest in the thermodynamics and foldingunfolding kinetics of BBL and peripheral subunit-binding domain homologues. Our results provide an unequivocal resolution to the fundamental controversy related to the global downhill folding scheme, whose applicability to other proteins should be critically reexamined. 10.1073/pnas.0708480105 Cooperative folding kinetics of BBL protein and peripheral subunit-binding domain homologues Wookyung Yu Kwanghoon Chung Mookyung Cheon Muyoung Heo Kyou-Hoon Han Sihyun Ham Iksoo Chang doi:10.1073/pnas.0708480105 Proceedings of the National Academy of Sciences, Vol. 105, No. 7. (19 February 2008), pp. 2397-2402. 2008-02-22T09:40:43-00:00 2008 Proceedings of the National Academy of Sciences 105 7 2397 2402 clip2 folding free-energy mc