Allosteric Signaling of Anesthetic Isoflurane Bound to LFA-1 Revealed by the PMT Model

Abstract

Allosteric signaling plays a critical role in biological systems. Mechanistic details of the signaling pathways, however, are often difficult to capture. The Perturbation-based Markovian Transmission (PMT) Model has been developed to mathematically describe the propagation of an initial perturbation through a protein network. Using the PMT model, we investigated how the binding of the anesthetic isoflurane to Lymphocyte Function-Associated Antigen-1 (LFA-1) could affect a remote functional site in LFA-1. The bound isoflurane in the LFA-1 crystal structure (pdb accession: 3F78) was treated as an explicit node in the protein network. Perturbation of the isoflurane node was determined to be consistent with perturbing residues with Cα within 5 A of isoflurane. We monitored the propagation of the isoflurane-induced perturbation through the protein, examined residues experiencing the top 5% of the perturbation flux, and found that several key residues (S139, L205, and N207) in the metal ion dependent adhesion site and intercellular adhesion molecule-1 binding interface were affected by isoflurane perturbation. Further investigation with the PMT model reveals two paths emanating from the bound isoflurane molecule. Residues identified along both paths experience significant deviation in crystal structure coordinates between open- and closed-conformation LFA-1. The binding of isoflurane seems to have stabilized such a path of contacts that prevent transitions from the closed to open conformation of LFA-1. Our study provided mechanistic details of isoflurane disruption of LFA-1 that are valuable for understanding of the secondary effects of anesthetics on the immune system. Supported by NIH (R01GM66358, R01GM56257, and R37GM049202).