Transient receptor potential-canonical 6 (TRPC6) calcium channels are currently the subject of intense investigation due to their roles in modulating smooth muscle tone in blood vessels and lung airways. TRPC6 channels are also proposed to mediate physiological processes in the kidney, immune system and central nervous system. We previously reported that binding of the immunophilin FKBP12 (FK506 binding protein-12 kDa) to a TRPC6 intracellular domain is a prerequisite for the formation of a multi-protein complex involved in channel regulation. This study also demonstrated that binding of FKBP12 to TRPC6 requires prior phosphorylation of Ser768 in the putative TRPC6 binding domain. To study the elements of molecular recognition in FKBP12 for the TRPC6 intracellular domain, we performed molecular dynamics simulations in explicit solvent on model complexes containing FKBP12 and the following: (i) the unphosphorylated wild-type TRPC6 intracellular binding domain, (ii) the wild-type TRPC6 binding domain containing a phosphorylated Ser768 residue, and (iii) TPRC6 peptides in which Ser768 was replaced with Asp or Glu. Simulations using the Generalized Born/Surface Area model (MM-GB/SA) predicted favorable binding and small conformational fluctuations for the FKBP12/phosphorylation Ser768 TRPC6 peptide complex, due to the strong interactions between the phosphate group and Lys44, and Lys47 residues in the FKBP12 binding site. Decomposition of the binding free energies into each amino acid residue identified additional important structural elements necessary for this protein-protein interaction.