The intermolecular interaction among the calcium sensor, calmodulin (CaM), and the C‐terminal domain of its cognate partner, transient receptor potential vanilloid 1 (TRPV1), plays a potential role in bone absorption… Click to show full abstract
The intermolecular interaction among the calcium sensor, calmodulin (CaM), and the C‐terminal domain of its cognate partner, transient receptor potential vanilloid 1 (TRPV1), plays a potential role in bone absorption and loss, which has been recognized as a new druggable target for osteoporosis therapy. Here, a synthetic strategy that integrates molecular modeling and chemometric analysis is used to statistically model and quantitatively predict the binding behavior of TRPV1 to CaM. The atomic‐level complex structures of CaM protein with the congeneric sequences of TRPV1 C‐terminus are modeled by virtual mutagenesis and structural refinement. Inter‐residue nonbonded interactions in the computationally modeled complex structures are analyzed, characterized, and correlated with experimentally measured affinity of CaM binding to a series of TRPV1 C‐terminal derivatives via both linear and nonlinear regression approaches. The built statistical predictors are then used to systematically investigate the independent residue‐pair interactions across CaM‐TRPV1 complex interface. Consequently, few TRPV1 C‐terminal residues are identified as potential hot spots that are primarily responsible for the CaM‐TRPV1 binding. Visual examination of CaM‐TRPV1 complex architecture reveals that these hot spot residues are evenly distributed through the core helical region of TRPV1 C‐terminus and involved in short‐range nonbonded interactions such as hydrogen bonds and salt bridges, which confer specificity to the complex recognition and association.
               
Click one of the above tabs to view related content.