ATPase Activity and ATP-dependent Conformational Change in the Co-chaperone HSP70/HSP90-organizing Protein (HOP)

Co-chaperones help to maintain cellular homeostasis by modulating the activities of molecular chaperones involved in protein quality control. The HSP70/HSP90-organizing protein (HOP) is a co-chaperone that cooperates with HSP70 and HSP90 in catalysis of protein folding and maturation in the cytosol. We show here that HOP has ATP-binding activity comparable to that of HSP70/HSP90, and that HOP slowly hydrolyzes ATP. Analysis of deletion mutants revealed that the ATPase domain of HOP is in the N-terminal TPR1-DP1-TPR2A segment. In addition, HOP changes its conformation in the presence of ATP. These results indicate that HOP is a unique co-chaperone that undergoes an ATP-dependent conformational change.     

Ketopiperazine-based renin inhibitors: optimization of the "C" ring

A systematic investigation of the S3 sub-pocket activity requirements was conducted. It was observed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3-sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with clog P's < or = 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.     

Atomistic uniaxial tension tests: investigating various many-body potentials for their ability to produce accurate stress strain curves using molecular dynamics simulations

Molecular dynamics simulations, which take place on the atomistic scale, are now being used to predict the influence of atomistic processes on macro-scale mechanical properties. However, there is a lack of clear understanding on which potential should be used when attempting to obtain these properties. Moreover, many MD studies that do test mechanical properties do not actually simulate the macro-scale laboratory tension tests used to obtain them. As such, the purpose of the current study was to evaluate the various types of potentials for their accuracy in predicting the mechanical properties of iron from an atomistic uniaxial tension test at room temperature. Results demonstrated that while EAM and MEAM potentials all under predicted the elastic modulus at room temperature, the Tersoff and ReaxFF potentials were significantly more accurate. Unlike EAM and MEAM, both the Tersoff and ReaxFF potentials are bond order based. Therefore, these results demonstrate the importance of considering bonding between atoms when modelling tensile tests. In addition, the ReaxFF potential also accurately predicted the Poisson's ratio, allowing for complete characterisation of the material's behaviour. Overall, these findings highlight the need to understand the capabilities and limitations of each potential before application to a problem outside of the initial intended use.