Effect of ligand binding on the intraminimum dynamics of proteins

Abstract

Effects of ligand binding on protein dynamics are studied via molecular dynamics (MD) simulations on two different enzymes, dihydrofolate reductase (DHFR) and triosephosphate isomerase (TIM), in their unliganded (free) and liganded states. Domain motions in MD trajectories are analyzed by collectivities and rotation angles along the principal components (PCs). DHFR in the free state has well-defined domain rotations, whereas rotations are slightly damped in the binary complex with nicotinamide adenine dinucleotide phosphate (NADPH), and remarkably distorted in the presence of NADP(+) , showing that NADP(+) is solely responsible for the loss of correlation of the domains in DHFR. Although mean square fluctuations of MD simulations in the same PC subspaces are similar for different ligation states, linear stochastic time series models show that backbone flexibility along the first five PCs is decreased upon NADPH and NADP(+) binding in subpicosecond scale. This shows that mobility of the protein along the PCs is closely related with intraminimum dynamics, and alterations in ligation states may change the intraminimum dynamics significantly. Low vibrational frequencies of the alpha-carbon atoms of DHFR are determined from the time series models of a larger number of low indexed PCs, and it is found that number of modes in the lowest frequencies is reduced upon ligand binding. A similar result is obtained for TIM in the unliganded and dihydroxyacetone phosphate bound states. We suggest that stochastic time series modeling is a promising method to be used in determining subtle perturbations in protein dynamics.