Molecular dynamics identifies semi-rigid domains in the PD-1 checkpoint receptor bound to its natural ligand PD-L1

Abstract

Cells in danger of being erroneously attacked by leucocytes express PD-L1 on their surface. These cells activate PD-1 on attacking leucocytes and send them to death, thus curbing erroneous, autoimmune attack. Unfortunately, cancer cells exploit this mechanism: By expressing PD-L1, they guard themselves against leucocyte attack and thereby evade immune clearance. Checkpoint inhibitors are drugs which re-enable immune clearance of cancer cells by blocking the binding of PD-L1 to PD-1 receptors. It is therefore of utmost interest to investigate these binding mechanisms. We use three 600 ns all-atom molecular dynamics simulations to scrutinize molecular motions of PD-1 with its binding partner, the natural ligand PD-L1. Usually, atomic motion patterns are evaluated against whole molecules as a reference, disregarding that such a reference is a dynamic entity by itself, thus degrading stability of the reference. As a remedy, we identify semi-rigid domains, lending themselves as more stable and reliable reference frames against which even minute differences in molecular motion can be quantified precisely. We propose an unsupervised three-step procedure. In previous work of our group and others, minute differences in motion patterns proved decisive for differences in function. Here, several highly reliable frames of reference are established for future investigations based on molecular motion.

A Comprehensive Computational Insight into the PD-L1 Binding to PD-1 and Small Molecules

“…The PD-1/PD-L1 adduct was also investigated by Kenn et al [ 66 ] performing MD simulations (three replicas of 600 ns) using the Amber99sb-ildn FF coupling with an unsupervised clustering method. They identified specific regions of the PD-1/PD-L1 complex forming stable clusters over time, which are hence named “semi-rigid domains”.…”

Clustering molecular dynamics conformations of the CC’-loop of the PD-1 immuno-checkpoint receptor

“…The right part of panel C shows the molecule rotated. (Images partly taken from [8] and [5] with permission). …”

“…This mechanism can also be blocked by modern drugs, immune-checkpoint-inhibitors, such as Pembrolizumab or Nivolumab. In previous work we have investigated their molecular action in detail [4] , [5] , [6] , [7] , [8] . Checkpoint-inhibitors are pharmacologically designed to bind to PD-1 without activating it.…”