Conformational Transition Pathway in the Inhibitor Binding Process of Human Monoacylglycerol Lipase

Abstract

Human monoacylglycerol lipase (MGL) catalyzes the hydrolysis of 2-arachidonoylglycerol to arachidonic and glycerol, which plays a pivotal role in the normal biological processes of brain. Co-crystal structure of the MGL in complex with its inhibitor, compound 1, shows that the helix a4 undergoes large-scale conformational changes in response to the compound 1 binding compared to the apo MGL. However, the detailed conformational transition pathway of the helix a4 in the inhibitor binding process of MGL has remained unclear. Here, conventional molecular dynamics (MD) and nudged elastic band (NEB) simulations were performed to explore the conformational transition pathway of the helix a4. Conventional MD simulations unveiled that the compound 1 induced the closed conformation of the active site of MGL, reduced the conformational flexibility of the helix a4, and elicited the large-scale conformational rearrangement of the helix a4, leading to the complete folding of the helix a4. Moreover, NEB simulations revealed that the conformational transition pathway of helix a4 underwent an almost 180°c ounter-clockwise rotation of the helix a4. Our computational results advance the structural and mechanistic understanding of the inhibitory mechanism.

Effects of Distal Mutations on the Structure, Dynamics and Catalysis of Human Monoacylglycerol Lipase

“…The C α atoms distance between the lid domain residues Phe-159 (helix α4) and Gly-210 (helix α6) may be used as a sensitive probe to analyze access to the hMGL active site 40 . The 14.7 Å distance is indicative of a fully open conformation, whereas a distance of 7.8 Å is indicative of a closed conformation.…”

Conserved movement of TMS11 between occluded conformations of LacY and XylE of the major facilitator superfamily suggests a similar hinge‐like mechanism

“…In this article, we have shown that more accurate positioning can be achieved using Δ‐distance mapping. This established method could have wide applicability as more conformational state data become available. The majority of the TMS segments, including TMS11, which display intradomain movement, independent of the two domains' alternating access movement, were found in close proximity to the interdomain linker helices.…”

“…In this article we use an established technique, Δ‐distance mapping, to compare structures in different conformational states. The concept of calculating Δ‐distance maps is not new, but the recent availability of multiple conformational states for MFS homologs, LacY and XylE, has created a new application area. In fact, the most recent version of Chimera, release 1.10, contains a new function called RR distance maps.…”

Membrane-assisted tariquidar access and binding mechanisms of human ATP-binding cassette transporter P-glycoprotein

“…The nudged elastic band (NEB) method, developed as a chainof-states approach, has been demonstrated to be an effective algorithm for investigating the pathways involved in the dynamic process of ligands access and binding (Bergonzo et al, 2011;Lu et al, 2014;Xing et al, 2019) as well as conformational changes of proteins in different states (Chen et al, 2014;Li et al, 2014). In NEB, a transition path is approximated with a string of images (or copies) of the system.…”