Biology:Calmodulin in target binding and recognition

Calmodulin (CaM) is a versatile protein involved in almost every cellular process, including apoptosis, metabolism, smooth muscle contraction, learning and memory formation, inflammation and immune response. A wide range of target proteins, or CaM binding targets (CaMBTs) play a key role in regulating those cellular processes through interaction with CaM. Among them, most require the presence of Ca²⁺. As the central part, CaM transduces and decodes transient extracellular calcium influxes in various frequencies and amplitudes. Binding of calcium ions causes large conformational changes in CaM, which further selectively binds and activates downstream CaM binding target proteins (CaMBTs), in addition to those independent of Ca²⁺.

Mechanism of target binding and recognition

There are several opinions of the binding mechanism between CaM and CaMBT. The binding between a CaM and a CaMBT involves conformational changes in both. The binding domain of the CaMBTs is usually disordered. Current research indicates that selective protein binding occurs through the mechanism of mutually induced conformational fit, which would explain how calcium dynamics in CaM would modulate its interaction.

Experimental and computational methods of studying target binding and recognition

Current research on CaM signaling and CaM–BT interaction includes experimental kinetic rate observations and coarse grain/all atom molecular dynamics simulations. Because protein signaling and protein–protein interaction is a new field of research, many observed interactions cannot be explained through experiment alone. The unification between simulation and experimental results is necessary to expand the predictive power of the theoretical approach and create general laws that explain the mechanics of signaling/protein–protein interactions.

The computational approach for modeling macro molecules is very resource intensive. The Hamiltonian equation in molecular dynamic software relates each atom to all other atoms in the system through kinetic, electrostatic, van der Waals, dihedral angle, bond, etc. energies. For example, calmodulin-binding domain of brain calmodulin-dependent protein kinase II alpha polypeptide contains 21 residues and 318 atoms. For a single time step, the molecular dynamics software must perform energy calculations between every atom in the polypeptide, which is ~100,000 calculations. Since the time step must be in the sub picosecond range (to insure stability), several million time steps must be performed to obtain meaningful data. To remedy the large number of calculations involved in all atom simulations, the coarse grain simulation technique can be used. Current work from the biophysics group at the University of Houston uses open source coarse-grained and all atomistic models of CaM and wildtype/mutated binding targets of CaMKII in their research.