5 research outputs found
The Dynamics of Ca2+ Ions within the Solvation Shell of Calbindin D9k
The encounter of a Ca2+ ion with a protein and its subsequent
binding to specific binding sites is an intricate process that cannot be fully
elucidated from experimental observations. We have applied Molecular Dynamics to
study this process with atomistic details, using Calbindin D9k (CaB) as a model
protein. The simulations show that in most of the time the Ca2+
ion spends within the Debye radius of CaB, it is being detained at the 1st and
2nd solvation shells. While being detained near the protein, the diffusion
coefficient of the ion is significantly reduced. However, due to the relatively
long period of detainment, the ion can scan an appreciable surface of the
protein. The enhanced propagation of the ion on the surface has a functional
role: significantly increasing the ability of the ion to scan the protein's
surface before being dispersed to the bulk. The contribution of this mechanism
to Ca2+ binding becomes significant at low ion concentrations,
where the intervals between successive encounters with the protein are getting
longer. The efficiency of the surface diffusion is affected by the distribution
of charges on the protein's surface. Comparison of the Ca2+
binding dynamics in CaB and its E60D mutant reveals that in the wild type (WT)
protein the carboxylate of E60 function as a preferred landing-site for the
Ca2+ arriving from the bulk, followed by delivering it to
the final binding site. Replacement of the glutamate by aspartate significantly
reduced the ability to transfer Ca2+ ions from D60 to the final
binding site, explaining the observed decrement in the affinity of the mutated
protein to Ca2+
A Molecular Dynamics Study of the Effect of Ca(2+) Removal on Calmodulin Structure
Calmodulin is a small (148 residues), ubiquitous, highly-conserved Ca(2+) binding protein serving as a modulator of many calcium-dependent processes. In this study, we followed, by means of molecular dynamics, the structural stability of the protein when one of its four bound Ca(2+) ions is removed, and compared it to a simulation of the fully Ca(2+) bound protein. We found that the removal of a single Ca(2+) ion from the N-lobe of the protein, which has a lower affinity for the ion, is sufficient to initiate a considerable structural rearrangement. Although the overall structure of the fully 4 Ca(2+) bound protein remained intact in the extended conformation, the Ca(2+)-removed protein changed its conformation into a compact state. The observation that the 3 Ca(2+) loaded protein assumes a compacted solution state is in accord with experimental observation that the NSCP protein, which binds only three Ca(2+) ions, is natively in a compact state. Examination of the folding dynamics reveals a cooperation between the C-lobe, N-lobe, and the interdomain helix that enable the conformation change. The forces driving this conformational change are discussed
Systematic search for the rate constants that control the exocytotic process from chromaffin cells by a Genetic Algorithm
A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology