Structural Basis for Weight Loss in Patients with Chronic Obstructive Pulmonary Disease: Modeling of Gly80 and Ser80 Variants of Human Group IID Phospholipase A2 and their Receptor Complexes

Abstract

Weight loss is a well known systemic manifestation of Chronic Obstructive Pulmonary Disease. a Gly80Ser mutation on human group IID secretory phospholipase A2 enhances expression of cytokines that are responsible for weight loss. In this study, we seek to establish the structural correlation of wild type and foresaid mutation with its function. Secretory phospholipase A2 with glycine and serine at eightieth positions and M‐type receptor were modeled. The enzymes were docked to the receptor and molecular dynamics was carried out to 40ns. Structural analysis shows the enzymes to be comprising of three helices (HI‐H3), two short helices (SH1 and SH2), five loops including a calcium binding loop (L1‐L5), and stabilized by seven disulfide bonds. The overall back bone folds of the two models are very similar with main chain RMSD of less than 1Å. Active site within the substrate binding channel shows catalytic triad of water‐His67‐ Asp112 which show hydrogen bonded network. The major structural differences between wild and mutant enzymes are: (1) loop‐L3 between H2 and H3 that bears the residue Gly80 in the wild type is flexible, being completely exposed to solvent and forms three hydrogen bonded interactions: (a) main chain nitrogen of Gly80 with hydroxyl group of Tyr86; (b) Oδ2 of Asp84 with amide nitrogen of Tyr82, and (c) polar contact between main chain oxygen atom of Gly80 and water molecule. Whereas, in the mutant enzyme the loop region between residues Ser80 and Arg87 adopts a relatively closed conformation with respect to the channel opening, where it is more rigid and stabilized by five hydrogen bonded interactions and two salt bridges. This along with the loss of hydrogen bond between Ser80 and Tyr86 provides flexibility to the loop; (2) conformation of loop in sPLA2‐Ser80 makes interfacial binding surface more planar thereby increasing compactness of the enzyme as indicated by decrease of volume by 2nm3, and (3) interfacial binding surface contact area and quality of interactions of the mutant enzyme is better with the receptor as compared to the wild type. Therefore, the structural differences delineated in this study are potential biophysical factors that determine the potency of wild and mutant enzymes with macrophage receptors, for respective functions of cytokine release resulting in clinical scenario of cachexia.Support or Funding InformationThis research was supported by Department of Science and Technology, Govt. of India: SR/FT/18.