Flap Dynamics in Aspartic Proteases: A Computational Perspective

Abstract

Recent advances in biochemistry and drug design have placed proteases as one of the critical target groups for developing novel small-molecule inhibitors. Among all proteases, aspartic proteases have gained significant attention due to their role in HIV/AIDS, malaria, Alzheimer's disease, etc. The binding cleft is covered by one or two β-hairpins (flaps) which need to be opened before a ligand can bind. After binding, the flaps close to retain the ligand in the active site. Development of computational tools has improved our understanding of flap dynamics and its role in ligand recognition. In the past decade, several computational approaches, for example molecular dynamics (MD) simulations, coarse-grained simulations, replica-exchange molecular dynamics (REMD) and metadynamics, have been used to understand flap dynamics and conformational motions associated with flap movements. This review is intended to summarize the computational progress towards understanding the flap dynamics of proteases and to be a reference for future studies in this field.

Exploring the flap dynamics of the South African HIV subtype C protease in presence of FDA‐approved inhibitors: MD study

“…In the current analysis, ATV attained flap tip distance values of slightly less than 8 Å and DRV-and LPV-complexes showed higher tendency to remain in semi-open conformation (Supporting Information Figure S3) while TPV displayed even smaller flap tip distances. Interestingly, all these drug complexes rarely achieved full closed conformations (5-6 Å) [60] which has been reported as an important characteristic of C-SA protease by experimental evidence. [7,65] The drug complexes displayed flap-tip distances of 7-9 Å and did not achieve 5-6 Å attained by Apo as shown in Supporting Information Figure S3A.…”

“…Flap dynamics of HIV‐1 PR is closely associated with the substrate binding and is therefore a crucial part of drug binding and effectiveness . Analyses of the RMSF plots indicates that flap dynamics play an important role and can be used to determine the functionalities of the FDA approved second generation drugs in C‐SA PR.…”

“…Flap dynamics of HIV-1 PR is closely associated with the substrate binding and is therefore a crucial part of drug binding and effectiveness. [60] Analyses of the RMSF plots indicates that flap dynamics play an important role and can be used to determine the functionalities of the FDA approved second generation drugs in C-SA PR. The movements of the flap region and other parts of the enzyme were further analysed by the principal component analyses (PCA) analysis in the latter part of the manuscript.…”

Aspartic peptidases of the pinewood nematode Bursaphelenchus xylophilus: Molecular characterization and in silico structural analysis

“…Aspartic peptidases are mostly secreted from cells as zymogens, inactive precursors of the active enzymes, which activate autocatalytically at acidic pH upon cleavage of the N-terminal pro-peptide. The detected extended loops projected over the clefts form the active site flaps, which encloses substrates and inhibitors in the active sites (Mahanti et al, 2016 (Kikuchi et al, 2009;Shinya et al, 2013). The N-terminal pro-peptide was predicted in 3-D structure of the three aspartic peptidases from B. xylophilus here described.…”

“…The N-and C-terminal domains, although structurally related by a 2-fold axis, have only limited sequence homology, except the vicinity of the active site that is located at the groove formed by the two lobes. The detected extended loops projected over the clefts form the active site flaps, which encloses substrates and inhibitors in the active sites (Mahanti et al, 2016). It is quite likely that secreted peptidases have essential roles in the success of B. xylophilus parasitism on pine trees.…”