Quantum chemical studies on nucleophilic sites in calcium ion bound zwitterionic calmodulin loops

Abstract

We perform quantum chemical (QC) calculations based on the density functional theory (DFT) approach for biologically relevant zwitterionic polypeptides, comprising of isolated calcium (Ca²⁺) ion bound EF-hand loops of calmodulin (CaM). The HOMO and the LUMO levels are observed to be dominated by terminal capping contributions which fall off exponentially in neighboring energy levels. These levels with negligible capping contributions are considered as HOMO⁻ and LUMO⁺. In loop 1 and loop 2 of CaM, HOMO⁻ and LUMO⁺ are dominated by acidic aspartates and polar residues whereas only polar side chains contribute in the energy levels of loop 3 and loop 4. We find that the HOMO⁻ of loop 3 shows strong localized electron density on the side chain phenyl ring of tyrosine. This is an indication of potential nucleophilic sites for tyrosine phosphorylation in CaM. Our calculation provides a systematic way of interpreting the functionality of zwitterionic polypeptides at physiological conditions from the electronic energy spectra. Moreover, the capping levels indicate possible device applications.