The Monoclonal Antibody Pembrolizumab Alters Dynamics of the Human Programmed Cell Death Receptor 1 (PD-1)

Tomasiak, Lisa; Karch, Rudolf; Schreiner, Wolfgang

doi:10.1109/bibm52615.2021.9669720

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…Molecular preparation and technical details of the molecular dynamics (MD) simulation have already been reported ( Tomasiak et al, 2021 ). In Sections 2.1 , 2.2 , we briefly recapitulate essential points for completeness.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously ( Tomasiak et al, 2021 ) all-atom MD simulations were performed with GROMACS 2021.2 ( Hess et al, 2008 ), using the Amber99sb-ildn force field ( Lindorff-Larsen et al, 2010 ) and an explicit water model. For the simulation box a rhombic dodecahedron was chosen with a minimum distance of 2 nm between the respective molecules and the box boundaries.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the residues 70 to 77, comprising the CC′-loop, are crucial for interaction with the natural ligand PD-L1 (Kundapura and Ramagopal, 2019), see Figure 2. Details of this interaction have been investigated experimentally by Zak (Zak et al, 2015) and in molecular dynamics studies by Liu (Liu et al, 2017) and our group (Roither et al, 2020;Tomasiak et al, 2020;Roither et al, 2021;Tomasiak et al, 2021).…”

Section: Molecular Structuresmentioning

confidence: 99%

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

Kenn

Karch

Tomasiak

et al. 2022

Front. Bioeng. Biotechnol.

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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.

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Section: Methodsmentioning

confidence: 99%