Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.

Randomness or noise in the motion of herding animals is more important than commonly assumed. We show through simulations that noise promotes the compactness of a herd by facilitating the breakup of small clusters in favor of a more compact whole, reducing the mean median distances to center (MMDC) for the herd. Adding noise to movement models can also decrease risk from predators emerging locally by reducing Domains of Danger (DODs); we specifically show that adding noise to the Voronoi (V) movement model gives favorable DOD results comparable to that of the Local Crowded Horizon (LCH) model. In addition, we show that adding noise to these models can significantly reduce risk from predators emerging outside the herding area through head-to-head competition in mixed herds, with effects that can be larger than the choice of model itself. Our results are consistent with recent observational studies in several different animal populations that suggest random motion plays a significant role in the movement of individuals within these groups. Because of its significance, noise must be considered whenever model effectiveness is discussed or comparisons between movement models are made.

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Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor belong to any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for such mutations. In this study, we present an analysis of 144 human enzymes containing 591 pathogenic missense variants, in which allosteric dynamic coupling of mutated positions with known active sites provides insights into a primary biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase), which contains 94 Gaucher disease-associated missense variants located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling due to the presence of missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.