[Review of] Charles W. Mills. The Racial Contract

Over the past few years I have read a number of articles by Professor Charles Mills. I have found him to be a stimulating thinker and lucid writer. In fact, I had the opportunity to use his article, Non-Cartesian Sums: Philosophy and the African American Experience (Teaching Philosophy, September 1994) in an NEH seminar that I conducted on multicultural approaches to Honor College teaching. Mills is a significant voice among the small cadre of Black philosophers committed to correction of and expansion beyond the Eurocentric myopia of professional philosophy. In his previous scholarship he demonstrates not only that he is insightful, critical and creative, but that he also grapples with questions and issues that few other philosophers, (including fellow Black philosophers), have dared to address. Of particular note is his provocative article, Do Black Men Have a Moral Duty to Marry Black Women (Journal of Social Philosophy, July 1994)

Modeling Conformational Ensembles of Slow Functional Motions in Pin1-WW

Protein-protein interactions are often mediated by flexible loops that experience conformational dynamics on the microsecond to millisecond time scales. NMR relaxation studies can map these dynamics. However, defining the network of inter-converting conformers that underlie the relaxation data remains generally challenging. Here, we combine NMR relaxation experiments with simulation to visualize networks of inter-converting conformers. We demonstrate our approach with the apo Pin1-WW domain, for which NMR has revealed conformational dynamics of a flexible loop in the millisecond range. We sample and cluster the free energy landscape using Markov State Models (MSM) with major and minor exchange states with high correlation with the NMR relaxation data and low NOE violations. These MSM are hierarchical ensembles of slowly interconverting, metastable macrostates and rapidly interconverting microstates. We found a low population state that consists primarily of holo-like conformations and is a “hub” visited by most pathways between macrostates. These results suggest that conformational equilibria between holo-like and alternative conformers pre-exist in the intrinsic dynamics of apo Pin1-WW. Analysis using MutInf, a mutual information method for quantifying correlated motions, reveals that WW dynamics not only play a role in substrate recognition, but also may help couple the substrate binding site on the WW domain to the one on the catalytic domain. Our work represents an important step towards building networks of inter-converting conformational states and is generally applicable