Rapid Sampling of Molecular Motions with Prior Information Constraints

Proteins are active, flexible machines that perform a range of different functions. Innovative experimental approaches may now provide limited partial information about conformational changes along motion pathways of proteins. There is therefore a need for computational approaches that can efficiently incorporate prior information into motion prediction schemes. In this paper, we present PathRover, a general setup designed for the integration of prior information into the motion planning algorithm of rapidly exploring random trees (RRT). Each suggested motion pathway comprises a sequence of low-energy clash-free conformations that satisfy an arbitrary number of prior information constraints. These constraints can be derived from experimental data or from expert intuition about the motion. The incorporation of prior information is very straightforward and significantly narrows down the vast search in the typically high-dimensional conformational space, leading to dramatic reduction in running time. To allow the use of state-of-the-art energy functions and conformational sampling, we have integrated this framework into Rosetta, an accurate protocol for diverse types of structural modeling. The suggested framework can serve as an effective complementary tool for molecular dynamics, Normal Mode Analysis, and other prevalent techniques for predicting motion in proteins. We applied our framework to three different model systems. We show that a limited set of experimentally motivated constraints may effectively bias the simulations toward diverse predicates in an outright fashion, from distance constraints to enforcement of loop closure. In particular, our analysis sheds light on mechanisms of protein domain swapping and on the role of different residues in the motion

Expression and Guidance in Schroeder’s Expressivist Semantics

Mark Schroeder’s expressivist program has made substantial progress in providing a compositional semantics for normative terms. This paper argues that it risks achieving this semantic progress at the cost of abandoning a key theoretical motivation for embracing expressivism in the first place. The problem can be summarized as a dilemma. Either Schroeder must allow that there are cases in which agents are in disagreement with one another, or can make valid inferences, but that these disagreements or inferences are not expressible in natural language; or his version of expressivism must abandon one of the key theoretical advantages expressivist theories seemed to possess over cognitivism, the ability to provide a very straightforward explanation of the action- and attitude-guiding role of normative judgments

Moral expressivism and sentential negation

This paper advances three necessary conditions on a successful account of sentential negation. First, the ability to explain the constancy of sentential meaning across negated and unnegated contexts (the Fregean Condition). Second, the ability to explain why sentences and their negations are inconsistent, and inconsistent in virtue of the meaning of negation (the Semantic Condition). Third, the ability of the account to generalize regardless of the topic of the negated sentence (the Generality Condition). The paper discusses three accounts of negation available to moral expressivists. The first – the ‘dominant commitment account’ – fails to meet the Fregean Condition. The two remaining accounts – one suggested by commitment semantics and the other by recent analyses of the ‘expression’ relation – satisfy all three conditions. Mark Schroeder’s argument that the dominant commitment account is the only option available to expressivists is considered and rejected