Calmodulin (CaM) and phosphatidylinositide-3 kinase (PI3Kα) are well known for 
their multiple roles in a series of intracellular signaling pathways and in the 
progression of several human cancers. Crosstalk between CaM and PI3Kα has been 
an area of intensive research. Recent experiments have shown that in 
adenocarcinoma, K-Ras4B is involved in the CaM-PI3Kα crosstalk. Based on 
experimental results, we have recently put forward a hypothesis that the 
coordination of CaM and PI3Kα with K-Ras4B forms a CaM-PI3Kα-K-Ras4B ternary 
complex, which leads to the formation of pancreatic ductal adenocarcinoma. 
However, the mechanism for the CaM-PI3Kα crosstalk is unresolved. Based on 
molecular modeling and molecular dynamics simulations, here we explored the 
potential interactions between CaM and the c/nSH2 domains of p85α subunit of 
PI3Kα. We demonstrated that CaM can interact with the c/nSH2 domains and the 
interaction details were unraveled. Moreover, the possible modes for the 
CaM-cSH2 and CaM-nSH2 interactions were uncovered and we used them to construct 
a complete CaM-PI3Kα complex model. The structural model of CaM-PI3Kα 
interaction not only offers a support for our previous ternary complex 
hypothesis, but also is useful for drug design targeted at CaM-PI3Kα 
protein-protein interactions.