Computational analysis of complement inhibitor compstatin using molecular dynamics
- PDF / 896,961 Bytes
- 9 Pages / 595.224 x 790.955 pts Page_size
- 59 Downloads / 220 Views
ORIGINAL PAPER
Computational analysis of complement inhibitor compstatin using molecular dynamics Didier Devaurs1
· Dinler A. Antunes2 · Lydia E. Kavraki2
Received: 21 January 2020 / Accepted: 14 July 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The complement system plays a major role in human immunity, but its abnormal activation can have severe pathological impacts. By mimicking a natural mechanism of complement regulation, the small peptide compstatin has proven to be a very promising complement inhibitor. Over the years, several compstatin analogs have been created, with improved inhibitory potency. A recent analog is being developed as a candidate drug against several pathological conditions, including COVID19. However, the reasons behind its higher potency and increased binding affinity to complement proteins are not fully clear. This computational study highlights the mechanistic properties of several compstatin analogs, thus complementing previous experimental studies. We perform molecular dynamics simulations involving six analogs alone in solution and two complexes with compstatin bound to complement component 3. These simulations reveal that all the analogs we consider, except the original compstatin, naturally adopt a pre-bound conformation in solution. Interestingly, this set of analogs adopting a pre-bound conformation includes analogs that were not known to benefit from this behavior. We also show that the most recent compstatin analog (among those we consider) forms a stronger hydrogen bond network with its complement receptor than an earlier analog. Keywords Compstatin · Complement system · Complement inhibition · Molecular dynamics
Introduction The complement system acts as the first line of defense in the immune system, as part of both innate and adaptive immunity [1]. It plays a major role in homeostasis by clearing foreign pathogens and compromised host cells [2]. The complement system is activated through several initiation pathways that produce strong opsonins, pro-inflammatory anaphylatoxins, and membrane attack complexes [3]. Complement activity is normally tightly regulated by various plasma and membrane proteins, such as complement receptor 1 and factor H [1]. Erroneous complement activation leads to tissue damage, causing or aggravating numerous
Lydia E. Kavraki
[email protected] 1
University of Grenoble Alpes, CNRS, Inria, Grenoble INP, LJK, 38000, Grenoble, France
2
Department of Computer Science, Rice University, 6100 Main St, Houston, TX 77005, USA
pathological conditions, such as heart attacks, strokes, burn injuries, Alzheimer’s disease, adult respiratory distress syndrome, and various autoimmune diseases [2, 4]. To prevent or remedy these undesirable effects, several complement inhibitors have been developed, targeting different steps of complement activation [3, 5, 6]. Thanks to its excellent efficacy, high specificity, low molecular weight, and ability to inhibit complement regardless of the initiation pathway, compstatin is considered
Data Loading...
