The rational design of T Cell Receptors (TCRs) for immunotherapy has stagnated due to a limited understanding of the dynamic physiochemical features of the TCR that elicit an immunogenic response. The physiochemical features of the TCR-peptide major histocompatibility complex (pMHC) bond dictate bond lifetime which, in turn, correlates with immunogenicity. Here, we: i) characterize the force-dependent dissociation kinetics of the bond between a TCR and a set of pMHC ligands using Steered Molecular Dynamics (SMD); and ii) implement a machine learning algorithm to identify which physiochemical features of the TCR govern dissociation kinetics. Our results demonstrate that the total number of hydrogen bonds between the CDR2β-MHC⍺(β), CDR1α-Peptide, and CDR3β-Peptide are critical features that determine bond lifetime. 

https://doi.org/10.1016/j.csbj.2022.06.048

A computational algorithm to assess the physiochemical determinants of T cell receptor dissociation kinetics

The rational design of T Cell Receptors (TCRs) for immunotherapy has stagnated due to a limited understanding of the dynamic physiochemical features of the TCR that elicit an immunogenic response. The physiochemical features of the TCR-peptide major histocompatibility complex (pMHC) bond dictate bond lifetime which, in turn, correlates with immunogenicity. Here, we: i) characterize the force-dependent dissociation kinetics of the bond between a TCR and a set of pMHC ligands using Steered Molecular Dynamics (SMD); and ii) implement a machine learning algorithm to identify which physiochemical features of the TCR govern dissociation kinetics. Our results demonstrate that the total number of hydrogen bonds between the CDR2b-MHCα(β), CDR1α-Peptide, and CDR3β-Peptide are critical features that determine bond lifetime. We propose that amino acid substitutions to these hypervariable regions of the TCR can efficiently manipulate immunogenicity and thus be used in the rational design of TCRs for immunotherapy.

https://www.biorxiv.org/content/biorxiv/early/2021/10/26/2021.10.25.465739.full.pdf

The Atomic-Level Physiochemical Determinants of T Cell Receptor Dissociation Kinetics

This work presents a novel parametrization for the ReaxFF formalism as a means to investigate reaction processes of chlorinated organic compounds. Force field parameters cover the chemical elements C, H, O, Cl and were obtained using a novel optimization approach involving relaxed potential energy surface scans as training targets. The resulting ReaxFF parametrization shows good transferability, as demonstrated on two independent ab initio validation sets. While this first part of our two-paper series focuses on force field parametrization, we apply our parameters to the simulation of chlorinated dibenzofuran formation and decomposition processes in Part II.

A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part I: Force Field Development.

Automatic potential energy surface (PES) exploration is important to a better understanding of reaction mechanisms. Existing automatic PES mapping tools usually rely on predefined knowledge or computationally expensive on-the-fly quantum-chemical calculations. In this work, we have developed the PESmapping algorithm for discovering novel reaction pathways and automatically mapping out the PES using merely one starting species is present. The algorithm explores the unknown PES by iteratively spawning new reactive molecular dynamics (RMD) simulations for species that it has detected within previous RMD simulations. We have therefore extended the RMD simulation tool ChemTraYzer2.1 (Chemical Trajectory Analyzer, CTY) for this PESmapping algorithm. It can generate new seed species, automatically start replica simulations for new pathways, and stop the simulation when a reaction is found, reducing the computational cost of the algorithm. To explore PESs with low-temperature reactions, we applied the acceleration method collective variable (CV)-driven hyperdynamics. This involved the development of tailored CV templates, which are discussed in this study. We validate our approach for known pathways in various pyrolysis and oxidation systems: hydrocarbon isomerization and dissociation (C4H7 and C8H7 PES), mostly dominant at high temperatures and low-temperature oxidation of n-butane (C4H9O2 PES) and cyclohexane (C6H11O2 PES). As a result, in addition to new pathways showing up in the simulations, common isomerization and dissociation pathways were found very fast: for example, 44 reactions of butenyl radicals including major isomerizations and decompositions within about 30 min wall time and low-temperature chemistry such as the internal H-shift of RO2 → QO2H within 1 day wall time. Last, we applied PESmapping to the oxidation of the recently proposed biohybrid fuel 1,3-dioxane and validated that the tool could be used to discover new reaction pathways of larger molecules that are of practical use.

Automatic Potential Energy Surface Exploration by Accelerated Reactive Molecular Dynamics Simulations: From Pyrolysis to Oxidation Chemistry.

Automatic potential energy surface (PES) exploration is important to better understand reaction mechanisms. Existing automatic PES mapping tools usually rely on predefined knowledge or on computationally expensive on-the-fly quantum-chemical calculations. In this work, we have developed a method for discovering novel reaction pathways and automatically mapping out the PES when only being given a starting species. We have therefore extended the reactive molecular dynamics simulation tool ChemTraYzer2.0 (Chemical Trajectory Analyzer, CTY) for this PES-mapping algorithm. To explore PESs with low-temperature reactions, we applied the acceleration method Collective Variable-driven Hyperdynamics (CVHD). This involved the development of tailored collective variable (CV) templates, which are discussed in this study. The PES mapping algorithm can generate new seed species, automatically start replica simulations for new pathways, and stop the simulation when a reaction has been found, reducing the computational cost of the algorithm. It is validated for known pathways in various pyrolysis and oxidation systems: hydrocarbon isomerization and dissociation (C4H7 and C8H7 PES), mostly dominant at high temperatures, low-temperature oxidation of n-butane (C4H9O2 PES) and cyclohexane (C6H11O2 PES). As a result, in addition to new pathways showing up in the simulations, common isomerization and dissociation pathways were found very fast: for example, 44 reactions of butenyl radicals including major isomerizations and decompositions within about 30 minutes wall time and low-temperature chemistry such as the internal H-shift of RO2 → QO2H within one day wall time. Furthermore, since CTY keeps track of all found geometries of the reactants, transition states, and products, PES mapping facilitates automated higher-level calculations without a priori knowledge. Lastly, we applied PES mapping to the oxidation of the recently proposed bio-hybrid fuel 1,3-dioxane and validated that the tool could be used to discover new reaction pathways of larger molecules that are of practical use. 

Automatic potential energy surface exploration by accelerated reactive MD simulations: from pyrolysis to oxidation chemistry

In our two-paper series, we first present the development of ReaxFF CHOCl parameters using the recently published ParAMS parametrization tool.In this second part, we update the reactive Molecular Dynamics - Quantum Mechanics coupling scheme ChemTraYzer and combine it with our new ReaxFF parameters from Part I to study formation and decomposition processes of chlorinated dibenzofurans.We introduce a self-learning method for recovering failed transition-state searches that improves the overall ChemTraYzer transition-state search success rate by 10 percentage points to a total of $48\%$.With ChemTraYzer, we automatically find and quantify more than 500 reactions using transition state theory and DFT.Among the discovered chlorinated dibenzofuran reactions are numerous reactions that are new to the literature.In three case studies, we discuss the set of reactions that are most relevant to the dibenzofuran literature: (i) bimolecular reactions of the chlorinated-dibenzofuran precursors phenoxy radical and 1,3,5-trichlorobenzene, (ii) dibenzofuran chlorination and pyrolysis, and (iii) oxidation of chlorinated dibenzofurans.

A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part II: A ChemTraYzer Study of Chlorinated Dibenzofuran Formation and Decomposition Processes.

The recently discovered, membrane–active peptide LBF14 contains several non–proteinogenic amino acids and is able to transform vesicles into tubule networks. The exact membrane interaction mechanis...

Determining structure and action mechanism of LBF14 by molecular simulation.

The front cover artwork is provided by Prof. K. Leonhard's group at RWTH Aachen University. The image shows ChemTraYzer, a virtual robot, while analyzing the reaction network related to the formation and oxidation of Chloro-Dibenzofuranes. Read the full text of the Research Article at 10.1002/cphc.202200783.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cphc.202300135

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A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part II: A ChemTraYzer Study of Chlorinated Dibenzofuran Formation and Decomposition Processes.

Determining structure and action mechanism of LBF14 by molecular simulation.

A Reactive Molecular Dynamics Study of Chlorinated Organic Compounds. Part II: A ChemTraYzer Study of Chlorinated Dibenzofuran Formation and Decomposition Processes.