Probing allostery is essential to understanding protein functions, and remains as an active research area in computational chemistry. Although many attentions have been given to searching for allosteric pathway or network within protein structure related to allostery, the potential role of or impact from individual amino acid residues to protein allostery remains underappreciated. Therefore, we developed a novel approach, referred as rigid residue scan (RRS), in which rigid-body constraint is implemented in molecular dynamics (MD) simulations to quantify the contribution of each residue to the overall protein dynamics. We applied the RRS to identify important allosteric residues of PDZ3 as a model system. Various indices based on cross-correlation matrices are used, which allow for two groups of residues with different functions to be identified. Furthermore, allostery in another allosteric protein PDZ2 is also examined as model system to advance RRS method combining with configurational entropy calculation and principal component analysis (PCA). Key residues of PDZ2 allostery were identified with good agreement with NMR studies. The quasi-harmonic and PCA of simulations without rigid residue perturbation showed coherent allosteric modes that project unbound and bound states into different space. The projection of simulations with rigid residue perturbation onto these coherent allosteric modes demonstrated the intrinsic shifting of ensemble distributions. More recently, 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 have been serving as guidance for further mutagenesis study of VVD and related LOV domains. Overall, our study has demonstrated that RRS is a valuable tool to effectively identify initial key residues for proteins with crystallographic structures and limited information of their allosteric mechanisms.

Correlating individual amino acid residues with protein allostery through rigid residue scan

254th National Meeting (2017)

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