Sequence, Structural Analysis and Metrics to Define the Unique Dynamic Features of the Flap Regions Among Aspartic Proteases

Abstract

Aspartic proteases are a class of hydrolytic enzymes that have been implicated in a number of diseases such as HIV, malaria, cancer and Alzheimer's. The flap region of aspartic proteases is a characteristic unique structural feature of these enzymes; and found to have a profound impact on protein overall structure, function and dynamics. Flap dynamics also plays a crucial role in drug binding and drug resistance. Therefore, understanding the structure and dynamic behavior of this flap regions is crucial in the design of potent and selective inhibitors against aspartic proteases. Defining metrics that can describe the flap motion/dynamics has been a challenging topic in literature. This review is the first attempt to compile comprehensive information on sequence, structure, motion and metrics used to assess the dynamics of the flap region of different aspartic proteases in "one pot". We believe that this review would be of critical importance to the researchers from different scientific domains.

A flap motif in human serine hydroxymethyltransferase is important for structural stabilization, ligand binding, and control of product release

“…In other organisms in which the DHFR lacks this flap region, such as human and E. coli, DHFR and TS exist as separate enzymes (44). A well-known flap motif is also found in HIV protease, which is well-recognized in its functional roles in pocket formation, ligand binding, and importantly enzyme catalysis in the enzyme homodimer (45).…”

Egress and invasion machinery of malaria: an in-depth look into the structural and functional features of the flap dynamics of plasmepsin IX and X

“…Flaps covering the active site have a dual role in Plm function: (i) structural, as interactions formed between a ligand and the aps stabilize the ligand-protease complex, and (ii) kinetic, as ap closing induces ligand binding and ap opening induces ligand release. 24 Previous work reported by our research group proposed parameters to measure the ap dynamics of Plm I-V, 23 which we have implemented in this study. In the absence of crystal structures of Plm IX-X, in silico models were generated for Plm IX-X and further renement of the generated models were performed using molecular dynamic simulations.…”

A dual target of Plasmepsin IX and X: Unveiling the atomistic superiority of a core chemical scaffold in malaria therapy

“…Previous studies have highlighted the crucial information associated with distance calculations particularly in aspartic proteases as it accurately describes the opening and closing of the flap‐structure exhibited as a “twisting motion.” The greatest difference observed between the maximum and minimum distance among all systems is more pronounced in the apo systems of PIX and PX as can be observed in Table , this may be attributed to the opening and closing motion being more defined in the absence of inhibitors. From the distance graphs presented of all six systems in Figures and , the fluctuation observed in the apo systems of PIX and PX, is clearly defined and further resembles the “Twisting motion.”…”