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Molecular dynamics and docking simulation of a natural variant of Activated Protein C with impaired protease
Pasqualina D'Ursi1, Alessandro Orro, Giulia Morra
1a Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche , 20090 Segrate , Italy.
Abstract:
Activated Protein C (APC) is a multifunctional serine protease, primarily known for its anticoagulant function in the coagulation system. Several studies have already elucidated its role in counteracting apoptosis and inflammation in cells, while significant effort is still ongoing for defining its involvement in sepsis. Earlier literature has shown that the antiseptic function of APC is mediated by its binding to leukocyte integrins, which is due to the presence of the integrin binding motif Arg-Gly-Asp at the N-terminus of the APC catalytic chain. Many natural mutants have been identified in patients with Protein C deficiency diagnosis including a variant of specificity pocket (Gly216Asp). In this work, we present a molecular model of the complex of APC with αVβ3 integrin obtained by protein-protein docking approach. A computational analysis of this variant is hereby presented, based on molecular dynamics and docking simulations, aiming at investigating the effects of the Gly216Asp mutation on the protein conformation and inferring its functional implications. Our study shows that such mutation is likely to impair the protease activity while preserving the overall protein fold. Moreover, superposition of the integrin binding motifs in wild-type and mutant forms suggests that the interaction with integrin can still occur and thus the mutant is likely to retain its antiseptic function related to the neutrophyl integrin binding. Therapeutic applications could result in this APC mutant which retains antiseptic function without anticoagulant side effects.
Insights
This study models a Gly216Asp mutation in Activated Protein C (APC). The mutant may retain antiseptic functions via integrin binding while reducing anticoagulant effects, suggesting therapeutic potential.
Area of Science:
- Biochemistry and Molecular Biology
- Computational Biology
- Pharmacology
Background:
- Activated Protein C (APC) is a serine protease with known anticoagulant, anti-apoptotic, and anti-inflammatory roles.
- APC's antiseptic function is linked to its Arg-Gly-Asp motif binding to leukocyte integrins.
- Natural Protein C deficiency mutants, like Gly216Asp, require functional characterization.
Purpose of the Study:
- To computationally model the complex of APC with αVβ3 integrin.
- To investigate the structural and functional effects of the Gly216Asp mutation on APC.
- To assess the potential therapeutic applications of the APC Gly216Asp mutant.
Main Methods:
- Protein-protein docking to model the APC-integrin complex.
- Molecular dynamics simulations to analyze the mutant's conformation.
- Docking simulations to evaluate integrin binding affinity of the mutant.
Main Results:
- The Gly216Asp mutation is predicted to impair APC's protease activity but preserve its overall protein fold.
- The mutant form likely retains the ability to interact with integrins via its binding motif.
- The APC Gly216Asp mutant may retain antiseptic functions without significant anticoagulant activity.
Conclusions:
- The Gly216Asp mutation in APC may offer a therapeutic strategy by uncoupling antiseptic from anticoagulant functions.
- This mutant warrants further investigation for its potential in treating conditions like sepsis.
- Computational modeling provides valuable insights into the functional implications of APC mutations.
