Dynamics-Based Peptide-MHC Binding Optimization by a Convolutional Variational Autoencoder: A Use-Case Model for CASTELO

An unsolved challenge in the development of antigen-specific immunotherapies is determining the optimal antigens to target. Comprehension of antigen-major histocompatibility complex (MHC) binding is paramount toward achieving this goal. Here, we apply CASTELO, a combined machine learning-molecular d...

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Vydáno v:	Journal of chemical theory and computation Ročník 17; číslo 12; s. 7962
Hlavní autoři:	Bell, David R, Domeniconi, Giacomo, Yang, Chih-Chieh, Zhou, Ruhong, Zhang, Leili, Cong, Guojing
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 14.12.2021
ISSN:	1549-9626, 1549-9626
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Shrnutí:	An unsolved challenge in the development of antigen-specific immunotherapies is determining the optimal antigens to target. Comprehension of antigen-major histocompatibility complex (MHC) binding is paramount toward achieving this goal. Here, we apply CASTELO, a combined machine learning-molecular dynamics (ML-MD) approach, to identify per-residue antigen binding contributions and then design novel antigens of increased MHC-II binding affinity for a type 1 diabetes-implicated system. We build upon a small-molecule lead optimization algorithm by training a convolutional variational autoencoder (CVAE) on MD trajectories of 48 different systems across four antigens and four HLA serotypes. We develop several new machine learning metrics including a structure-based anchor residue classification model as well as cluster comparison scores. ML-MD predictions agree well with experimental binding results and free energy perturbation-predicted binding affinities. Moreover, ML-MD metrics are independent of traditional MD stability metrics such as contact area and root-mean-square fluctuations (RMSF), which do not reflect binding affinity data. Our work supports the role of structure-based deep learning techniques in antigen-specific immunotherapy design.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1549-9626 1549-9626
DOI:	10.1021/acs.jctc.1c00870