The ab initio fragment molecular orbital (FMO) calculations were performed for retinoid X receptor (RXR) complexes with its ligand 9-cis retinoic acid (9cRA) and steroid receptor coactivator-1 (SRC1) to examine the influence of mutations in transcriptional activation function 2 activating domain core (AF2C) of RXR on molecular interactions between 9cRA liganded RXR and SRC1 coactivator. The RXR-SRC1 interactions in three types of RXR-9cRA-SRC1 complexes, namely, a wild type (WT), a mutant whose Glu453 of AF2C was substituted by Lys (E453K), and another mutant whose Glu456 of AF2C was substituted by Lys (E456K), were compared. Through the comparison of WT, E453K, and E456K, possible causes for a marked decrease in the transcriptional activity of RXR by the mutation of Glu453, which is known as a highly conserved charged residue of AF2C, were discussed. It was quantitatively demonstrated that the strength of the RXR-SRC1 interaction correlates with the degree of the transcriptional activation (WT > E456K > E453K). In E453K, the RXR-SRC1 interaction was substantially reduced by the AF2C-SRC1 repulsive interaction, and the charge transfer (CT) from RXR to SRC1 was also inhibited by the decreased electron donation from AF2C to SRC1. Our findings suggest that the inhibitions of the local RXR-SRC1 interaction via AF2C and of the local CT from RXR to SRC1 via AF2C would be the possible causes for the marked decrease in the transcriptional activity of RXR.