Ligand Binding, Protein Fluctuations, and Allosteric Free Energy

Although the importance of protein dynamics in protein function is generally recognized, the role of protein fluctuations in allosteric effects scarcely has been considered. To address this gap, the Kullback-Leibler divergence (Dx) between protein conformational distributions before and after ligand binding was proposed as a means of quantifying allosteric effects in proteins. Here, previous applications of Dx to methods for analysis and simulation of proteins are first reviewed, and their implications for understanding aspects of protein function and protein evolution are discussed. Next, equations for Dx suggest that k_{B}TDx should be interpreted as an allosteric free energy -- the free energy associated with changing the ligand-free protein conformational distribution to the ligand-bound conformational distribution. This interpretation leads to a thermodynamic model of allosteric transitions that unifies existing perspectives on the relation between ligand binding and changes in protein conformational distributions. The definition of Dx is used to explore some interesting mathematical relations among commonly recognized thermodynamic and biophysical quantities, such as the total free energy change upon ligand binding, and ligand-binding affinities for individual protein conformations. These results represent the beginnings of a theoretical framework for considering the full protein conformational distribution in modeling allosteric transitions. Early applications of the framework have produced results with implications both for methods for coarsed-grained modeling of proteins, and for understanding the relation between ligand binding and protein dynamics.Comment: 18 pages; 7 figures; Second International Congress of the Biocomputing and Physics of Complex Systems Research Institute, Zaragoza, Spain, 8-11 Feb 2006; increase breadth of review of methods for analysis of allosteric mechanisms; Add AIP in press; fix missing kTs in equation

Quantum crystallographic charge density of urea

Standard X-ray crystallography methods use free-atom models to calculate mean unit cell charge densities. Real molecules, however, have shared charge that is not captured accurately using free-atom models. To address this limitation, a charge density model of crystalline urea was calculated using high-level quantum theory and was refined against publicly available ultra high-resolution experimental Bragg data, including the effects of atomic displacement parameters. The resulting quantum crystallographic model was compared to models obtained using spherical atom or multipole methods. Despite using only the same number of free parameters as the spherical atom model, the agreement of the quantum model with the data is comparable to the multipole model. The static, theoretical crystalline charge density of the quantum model is distinct from the multipole model, indicating the quantum model provides substantially new information. Hydrogen thermal ellipsoids in the quantum model were very similar to those obtained using neutron crystallography, indicating that quantum crystallography can increase the accuracy of the X-ray crystallographic atomic displacement parameters. The results demonstrate the feasibility and benefits of integrating fully periodic quantum charge density calculations into ultra high-resolution X-ray crystallographic model building and refinement.Comment: 40 pages, 4 figures, 6 table

Concordance of Zp×ZpZ_p\times\Z_p actions on S4S^4

We consider locally linear Z_p x Z_p actions on the four-sphere. We present simple constructions of interesting examples, and then prove that a given action is concordant to its linear model if and only if a single surgery obstruction taking to form of an Arf invariant vanishes. We discuss the behavior of this invariant under various connected-sum operations, and conclude with a brief discussion of the existence of actions which are not concordant to their linear models

Regional VARs and the channels of monetary policy

We find that the magnitudes of the regional effects of monetary policy were considerably dampened during the Volcker-Greenspan era. Further, regional differences in the depths of monetary-policy-induced recessions are related to the concentration of the banking sector, whereas differences in the total cost of these recessions are related to industry mix.Monetary policy

Discordant City Employment Cycles

The national economy is often described as having a business cycle over which aggregate output enters and exits distinct expansion and recession phases. Analogously, national employment cycles in and out of its own expansion and contraction phases, which are closely related to the business cycle. This paper estimates city-level employment cycles for 58 large U.S. cities and documents the substantial cross-city variation in the timing, lengths, and frequencies of their employment contractions. It also shows how the spread of city-level contractions associated with U.S. recessions has tended to follow recession-specific geographic patterns. In addition, cities within the same state or region have tended to have similar employment cycles. There is no evidence, however, that similarities in employment cycles are related to similarities in industry mix. This suggests that the U.S. employment and business cycles has a spatial dimension that is independent of broad industry-level fluctuations.

Structural breaks and regional disparities in the transmission of monetary policy

Using a regional VAR, we find large differences in the effects of monetary policy shocks across regions of the United States. We also find that the region-level effects of monetary policy differ a great deal between the pre-Volcker and Volcker-Greenspan periods in terms of their depth and length. The two sample periods also yield very different rankings of the regions in terms of the effects of monetary policy. Our regional VAR also suggests that aggregate VARs that ignore regional variations can suffer from severe aggregation bias. We use the results of our regional VAR to find evidence that recession depth related to the banking concentration and that the total cost of recession is related to the industry mix. Finally, we demonstrate that the differences between the two sample periods are due to changes in the mechanism by which monetary policy shocks are propagated.Monetary policy ; Regional economics ; Economic conditions