When proteins are solvated in electrolyte solutions that contain alkali ions, the ions interact mostly with carboxylates on the protein surface. Correctly accounting for alkali-carboxylate interactions is thus important for realistic simulations of proteins. Acetates are the simplest carboxylates that are amphipathic, and experimental data for alkali acetate solutions is available and can be compared with observables obtained from simulations. We carried out molecular dynamics simulations of alkali acetate solutions using polarizable and non-polarizable forcefields, and examined the ion-acetate interactions. In particular, activity coefficients and association constants were studied in a range of concentrations (0.03, 0.1, and 1 M). In addition, quantummechanics (QM) based energy decomposition analysis was performed in order to estimate the contribution of polarization, electrostatics, dispersion and QM (non-classical) effects on the cation-acetate and cation-water interactions. Simulations of Li-acetate solutions in general overestimated the binding of Li + and acetates. In lower concentrations, the activity coefficients of alkali-acetate solutions were too high, which is suggested to be due to the simulation protocol and not the forcefields. Energy decomposition analysis suggested that improvement of the forcefield parameters to enable accurate simulations of Li-acetate solutions can be achieved, but may require the use of a polarizable forcefield. Importantly, simulations with some ion parameters could not reproduce the correct ion-oxygen distances, which calls for caution in the choice of ion parameters when protein simulations are performed in electrolyte solutions.
Inhibition of cyclin dependent kinases (CDKs) 4 and 6 prevent cells from entering the synthesis phase of the cell cycle. CDK4 and 6 are therefore important drug targets in various cancers. The selective CDK4/6 inhibitor palbociclib is approved for the treatment of breast cancer and has shown activity in a cellular model of mixed lineage leukaemia (MLL)‐rearranged acute myeloid leukaemia (AML). We studied the interactions of palbociclib and CDK6 using molecular dynamics simulations. Analysis of the simulations suggested several interactions that stabilized the drug in its binding site and that were not observed in the crystal structure of the protein‐drug complex. These included a hydrogen bond to His 100 that was hitherto not reported and several hydrophobic contacts. Evolutionary‐based bioinformatic analysis was used to suggest two mutants, D163G and H100L that would potentially yield drug resistance, as they lead to loss of important protein–drug interactions without hindering the viability of the protein. One of the mutants involved a change in the glycine of the well‐conserved DFG motif of the kinase. Interestingly, CDK6‐dependent human AML cells stably expressing either mutant retained sensitivity to palbociclib, indicating that the protein‐drug interactions are not affected by these. Furthermore, the cells were proliferative in the absence of palbociclib, indicating that the Asp to Gly mutation in the DFG motif did not interfere with the catalytic activity of the protein.
This paper presents an environment for molecular visualization with multi-projection and collaboration capabilities between geographically dispersed research groups. It was drafted a hardware and software architecture whose purpose is to reduce the negative effects of the delay in communication inherent longdistance networks.
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