Allostery is one of the fundamental properties of proteins, and considered as “second secret of life”, only second to genetic code. Despite its importance, the understanding and predicting power of protein allostery are still limited due to its elusive nature. Main challenges in examining protein allostery include effectively narrowing down residues for further site-directed mutagenesis study and probing conformational space accessible for proteins throughout allosteric mechanism. Recently, we developed a novel simulation method, named as rigid residue scanning (RRS) to systematically assess the contribution from each individual residue to overall protein dynamics. In RRS method, rigid body constraint was applied on each residue to remove internal degrees of freedom in separate molecular dynamics (MD) simulations. All the RRS simulations were analyzed and compared to shed light on the relationship between protein dynamics and individual residues. We applied RRS method to explore the allosteric mechanism of VIVID (VVD) protein from Light-Oxygen-Voltage (LOV) domains in circadian clock system. Upon blue light activation, VVD forms a covalent bond with its cofactor flavin adenine dinucleotide (FAD) and undergoes significant conformational change from dark-state to light-state. Using RRS method, key residues were identified with distinctive impacts on dark- and light-states, respectively. Clustering analysis of a two-dimensional distribution of VVD RRS simulations with reference to deviations from dark- and light-states leads to 15 representative structures, and reveal a hidden conformational region. Our findings could serve as guidance for further mutagenesis study of VVD and related LOV domains.

Surveying key residues for protein allostery using rigid residue scan method

253rd National Meeting (2017)

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