Study of the Allosteric Mechanism of Human Mitochondrial Phenylalanyl-tRNA Synthetase by Transfer Entropy via an Improved Gaussian Network Model and Co-evolution Analyses

Abstract

We propose an improved transfer entropy approach called the dynamic version of the force constant fitted Gaussian network model based on molecular dynamics ensemble (dfcfGNM MD ) to explore the allosteric mechanism of human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS), one of the aminoacyl-tRNA synthetases that play a crucial role in translation of the genetic code. The dfcfGNM MD method can provide reliable estimates of the transfer entropy and give new insights into the role of the anticodon binding domain in driving the catalytic domain in aminoacylation activity and into the effects of tRNA binding and residue mutation on the enzyme activity, revealing the causal mechanism of the allosteric communication in hmPheRS. In addition, we incorporate the residue dynamic and co-evolutionary information to further investigate the key residues in hmPheRS allostery. This study sheds light on the mechanisms of hmPheRS allostery and can provide important information for related drug design.A minoacyl-tRNA synthetases (aaRSes) are the universally distributed enzymes that play a crucial role in genetic code translation by means of covalent attachment of amino acids to their cognate tRNAs. 1 Human mitochondrial phenylalanyl-tRNA synthetase (hmPheRS), because it has a minimum set of structural domains capable of aminoacylation and being involved in various central nervous system (CNS) diseases like autosomal recessive spastic paraplegia, epileptic encephalopathy, infantile mitochondrial Alpers encephalopathy, etc., 2−5 has attracted a great deal of attention. 6−8 hmPheRS with a single chain is the smallest known member of class II aaRS. The structures of hmPheRS in tRNA-free and -bound states have been experimentally determined, which are composed of four major functional regions and several motifs as shown in Figure 1. The corresponding function annotations are listed in Table 1. Experiments found that certain mutations in hmPheRS's anticodon binding domain (ABD) can significantly affect the catalytic efficiency of its active sites in the catalytic domain (CAD), although the two sites are separated by ≤80 Å. 6,7 Structural studies, including ours, suggest the conformational flexibility of the functional regions and the long-range allosteric couplings between the domains are essential for hmPheRS's aminoacylation activity. 9,10 With regard to allostery, recent findings show it is entropic in nature and depends on the information transfer between two sites through residues' coordinated fluctuations. 11 Currently, the molecular mechanism by which the long-range allosteric

Dynamic Insights into the Self-Activation Pathway and Allosteric Regulation of the Orphan G-Protein-Coupled Receptor GPR52

“…TE is an effective method for the study of protein allosteric activity, where the time-delayed correlation is introduced to reveal the driver–driven relations between residue pairs. , According to the formulation proposed by Schreiber, the TE can be expressed as T i → j ( τ ) = S ( Δ R j false( t + τ false) | Δ R j false( t false) ) − S ( Δ R j false( t + τ false) | Δ R i false( t false) , Δ R j false( t false) ) where S (Δ R j ( t + τ)|Δ R j ( t )) is the conditional entropy of Δ R j ( t + τ) at time t + τ given the values of Δ R j ( t ) at time t , and S (Δ R j ( t + τ)|Δ R i ( t ), Δ R j ( t )) is the conditional entropy of Δ R j ( t + τ) at time t + τ given the values of Δ R i ( t ) and Δ R j ( t ) at time t . The difference shows the amount of entropy reduced in the trajectory of residue j due to knowledge of the past values of residue i .…”