Mapping the Dynamics Landscape of Conformational Transitions in Enzyme: The Adenylate Kinase Case

Abstract

Conformational transition describes the essential dynamics and mechanism of enzymes in pursuing their various functions. The fundamental and practical challenge to researchers is to quantitatively describe the roles of large-scale dynamic transitions for regulating the catalytic processes. In this study, we tackled this challenge by exploring the pathways and free energy landscape of conformational changes in adenylate kinase (AdK), a key ubiquitous enzyme for cellular energy homeostasis. Using explicit long-timescale (up to microseconds) molecular dynamics and bias-exchange metadynamics simulations, we determined at the atomistic level the intermediate conformational states and mapped the transition pathways of AdK in the presence and absence of ligands. There is clearly chronological operation of the functional domains of AdK. Specifically in the ligand-free AdK, there is no significant energy barrier in the free energy landscape separating the open and closed states. Instead there are multiple intermediate conformational states, which facilitate the rapid transitions of AdK. In the ligand-bound AdK, the closed conformation is energetically most favored with a large energy barrier to open it up, and the conformational population prefers to shift to the closed form coupled with transitions. The results suggest a perspective for a hybrid of conformational selection and induced fit operations of ligand binding to AdK. These observations, depicted in the most comprehensive and quantitative way to date, to our knowledge, emphasize the underlying intrinsic dynamics of AdK and reveal the sophisticated conformational transitions of AdK in fulfilling its enzymatic functions. The developed methodology can also apply to other proteins and biomolecular systems.

Data-guided Multi-Map variables for ensemble refinement of molecular movies

“…the open state based on the literature. [88][89][90] As shown in Fig. 6, the expected trends are retained, but…”

“…[88][89][90] Notably, apo-ADK's closed state (state B), is less favorable than apo-ADK's open state (state A). Conversely, holo-ADK's closed state is more favorable than…”

High Transmembrane Voltage Raised by Close Contact Initiates Fusion Pore

“…The lipid bilayers were generated by Membrane Builder online service (Jo et al, 2008, 2009). The simulation system was set up following a similar procedure in our previous studies (Li et al, 2010, 2011, 2015; Lai et al, 2015; Xu et al, 2015). The system was solvated in a ~23 × 23 × 20 nm 3 TIP3P (Jorgensen et al, 1983) water box, with ~210,000 water molecules and potassium ions added to neutralize the system.…”

Enzymatic evolution driven by entropy production

“…However, there is experimental evidence (3) showing that enzymatic processes take place along just one path (see Fig.1). For instance, processes mediated by adenylate kinase (AdK) arise along only one possible path having multiple intermediate conformations that may facilitate a rapid transition (4). It has been argued that relatively small free-energy differences between conformations could improve the fine control of transitions by environmental perturbations and signaling (5).…”