Computational Studies on Cholinesterases: Strengthening our Understanding of the Integration of Structure, Dynamics and Function
Joel L. Sussman and Israel Silman [1]
Molecular Tour
Computational approaches have proved valuable in elucidating structure/function relationships in the cholinesterases in the context of their unusual three-dimensional structure. In this review we survey several recent studies that have enhanced our understanding of how these enzymes function, and have utilized computational approaches both to modulate their activity and to improve the design of lead compounds for their inhibition.
Solution of the crystal structure of Torpedo californica acetylcholinesterase (TcAChE) in 1991 (Sussman et al., 1991), revealed a three-dimensional structure that was wholly unanticipated. Despite the fact that AChE is one of the most rapid enzymes known, operating at a speed approaching diffusion control (Bazelyansky et al., 1986; Rosenberry, 1975), its active site is deeply buried, at the bottom of a long and narrow gorge, whose cross-section, at its narrowest point, is significantly smaller than the cross-section of the quaternary group of acetylcholine (ACh). Subsequent solution of the crystal structures of mouse (m) (Bourne et al., 1995), Electrophorus electricus (Ee) (Bourne et al., 1999; Raves et al., 1998), human (h) (Cheung et al., 2012; Kryger et al., 2000), Drosophila melanogaster (Dm) (Harel et al., 2000), Bungarus fasciatus (Bf) (Bourne et al., 2015), and Anopheles gambiae (Ag) (Cheung et al., 2018; Han et al., 2018) AChEs, as well as that of human serum butyrylcholinesterase (hBChE) (Nicolet et al., 2003), revealed highly homologous structures. The crystal structures of the cholinesterases (ChEs) raised cogent questions with respect to the coupling of the structure of the enzymes, together with their dynamics, to their catalytic activity, and to the way in which inhibitors, some of which are large and rigid, bind to, and disassociate from them. These topics have been covered extensively in earlier reviews (Silman and Sussman, 2008; Xu et al., 2017). However, as computing power has continued to grow, databases have expanded, and increasingly sophisticated algorithms have been developed, problems become accessible that had previously seemed unapproachable (Fuxreiter, 2015). In the following, after briefly surveying the structure and dynamics of the ChEs, taking TcAChE as the prototypic case, we wish to briefly present and discuss some recent studies that cover various aspects of these topics.
References
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