Protein folding disorders: Toward a basic biological paradigm

Abstract

Mechanistic ‘physics’ models of protein folding fail to account for the observed spectrum and rate of protein folding and aggregation disorders in human populations, showing that more appropriately in vivo paradigms reflecting biological and other embedding contexts are needed for understanding the etiology, prevention, and treatment of these diseases. Here, a topological rate distortion analysis is applied to the problem that is analogous to Tlusty (2007) elegant exploration of the genetic code. A ‘developmental’ perspective sees the rate distortion function as a temperature analog in a spontaneous symmetry breaking argument, and permits incorporation of external factors as catalysts, driving the system to different possible outcomes via a nonequilibrium empirical Onsager treatment, viewed as a kind of dynamic regression equation. The formalism produces large-scale, quasi-equilibrium ‘resilience’ states representing normal and pathological protein folding. Generalization to long times produces diffusion models of protein folding disorders in which epigenetic or life history factors determine the rate of onset of dysfunction.