Modeling the effect of pathogenic mutations on the conformational landscape of protein kinases

Most proteins assume different conformations to perform their cellular functions. This conformational dynamics is physiologically regulated by binding events and post-translational modifications, but can also be affected by pathogenic mutations. Atomistic molecular dynamics simulations complemented by enhanced sampling approaches are increasingly used to probe the effect of mutations on the conformational dynamics and on the underlying conformational free energy landscape of proteins. In this short review we discuss recent successful examples of simulations used to understand the molecular mechanism underlying the deregulation of physiological conformational dynamics due to non-synonymous single point mutations. Our examples are mostly drawn from the protein kinase family

The INTERNODES method for applications in contact mechanics and dedicated preconditioning techniques

The mortar finite element method is a well-established method for the numerical solution of partial differential equations on domains displaying non-conforming interfaces. The method is known for its application in computational contact mechanics. However, its implementation remains challenging as it relies on geometrical projections and unconventional quadrature rules. The INTERNODES (INTERpolation for NOn-conforming DEcompositionS) method, instead, could overcome the implementation difficulties thanks to flexible interpolation techniques. Moreover, it was shown to be at least as accurate as the mortar method making it a very promising alternative for solving problems in contact mechanics. Unfortunately, in such situations the method requires solving a sequence of ill-conditioned linear systems. In this paper, preconditioning techniques are designed and implemented for the efficient solution of those linear systems

Soil C and N Changes with Afforestation of Grasslands Across Gradients of Precipitation and Plantation Age

Afforestation, the conversion of unforested lands to forests, is a tool for sequestering anthropogenic carbon dioxide into plant biomass. However, in addition to altering biomass, afforestation can have substantial effects on soil organic carbon (SOC) pools, some of which have much longer turnover times than plant biomass. An increasing body of evidence suggests that the effect of afforestation on SOC may depend on mean annual precipitation (MAP). The goal of this study was to test how labile and bulk pools of SOC and total soil nitrogen (TN) change with afforestation across a rainfall gradient of 600–1500 mm in the Rio de la Plata grasslands of Argentina and Uruguay. The sites were all former grasslands planted with Eucalyptus spp. Overall, we found that afforestation increased (up to 1012 kg C·ha−1·yr−1) or decreased (as much as 1294 kg C·ha−1·yr−1) SOC pools in this region and that these changes were significantly related to MAP. Drier sites gained, and wetter sites lost, SOC and TN (r2 = 0.59, P = 0.003; and r2 = 0.57, P = 0.004, respectively). Labile C and N in microbial biomass and extractable soil pools followed similar patterns to bulk SOC and TN. Interestingly, drier sites gained more SOC and TN as plantations aged, while losses reversed as plantations aged in wet sites, suggesting that plantation age in addition to precipitation is a critical driver of changes in soil organic matter with afforestation. This new evidence implies that longer intervals between harvests for plantations could improve SOC storage, ameliorating the negative trends found in humid sites. Our results suggest that the value of afforestation as a carbon sequestration tool should be considered in the context of precipitation and age of the forest stand

Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations

p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity. Our study describes for the first time the molecular effects of different regulators of the enzymatic activity, and provides an integrative picture of the activation mechanism that explains the seemingly contradictory X-ray and NMR data

La experiencia de Dios del pueblo kuna

Hablar de la experiencia de Dios del pueblo Kuna, a pesar de ser nosotros hijos de esa cultura, no nos resulta nada fácil, ya que ésto implica un estudio serio y profundo, porque habría que estudiar todas las mitologías, la simbología y el lenguaje especializado; elementos éstos cuyo estudio implica verdaderos tratados con dedicación de muchísimos años