We investigate small sequence adjustments (of one or a few amino acids) that induce large conformational transitions between distinct and stable folds of proteins. Such transitions are intriguing from evolutionary and protein-design perspectives. They make it possible to search for ancient protein structures or to design protein switches that flip between folds and functions. A network of sequence flow between protein folds is computed for representative structures of the Protein Data Bank. The computed network is dense, on an average each structure is connected to tens of other folds. Proteins that attract sequences from a higher than expected number of neighboring folds are more likely to be enzymes and alpha/beta fold. The large number of connections between folds may reflect the need of enzymes to adjust their structures for alternative substrates. The network of the Cro family is discussed, and we speculate that capacity is an important factor (but not the only one) that determines protein evolution. The experimentally observed flip from all alpha to alpha + beta fold is examined by the network tools. A kinetic model for the transition of sequences between the folds (with only protein stability in mind) is proposed. Proteins 2010. © 2009 Wiley-Liss, Inc.
sábado, 7 de noviembre de 2009
Computational exploration of the network of sequence flow between protein structures
We investigate small sequence adjustments (of one or a few amino acids) that induce large conformational transitions between distinct and stable folds of proteins. Such transitions are intriguing from evolutionary and protein-design perspectives. They make it possible to search for ancient protein structures or to design protein switches that flip between folds and functions. A network of sequence flow between protein folds is computed for representative structures of the Protein Data Bank. The computed network is dense, on an average each structure is connected to tens of other folds. Proteins that attract sequences from a higher than expected number of neighboring folds are more likely to be enzymes and alpha/beta fold. The large number of connections between folds may reflect the need of enzymes to adjust their structures for alternative substrates. The network of the Cro family is discussed, and we speculate that capacity is an important factor (but not the only one) that determines protein evolution. The experimentally observed flip from all alpha to alpha + beta fold is examined by the network tools. A kinetic model for the transition of sequences between the folds (with only protein stability in mind) is proposed. Proteins 2010. © 2009 Wiley-Liss, Inc.
Weak convergence in the Prokhorov metric of methods for stochastic differential equations
We consider the weak convergence of numerical methods for stochastic differential equations (SDEs). Weak convergence is usually expressed in terms of the convergence of expected values of test functions of the trajectories. Here we present an alternative formulation of weak convergence in terms of the well-known Prokhorov metric on spaces of random variables. For a general class of methods we establish bounds on the rates of convergence in terms of the Prokhorov metric. In doing so, we revisit the original proofs of weak convergence and show explicitly how the bounds on the error depend on the smoothness of the test functions. As an application of our result, we use the Strassen–Dudley theorem to show that the numerical approximation and the true solution to the system of SDEs can be re-embedded in a probability space in such a way that the method converges there in a strong sense. One corollary of this last result is that the method converges in the Wasserstein distance, another metric on spaces of random variables. Another corollary establishes rates of convergence for expected values of test functions, assuming only local Lipschitz continuity. We conclude with a review of the existing results for pathwise convergence of weakly converging methods and the corresponding strong results available under re-embedding.
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