Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Poster Abstracts

ASSESSING THE IMPACTS OF SMALL VARIANTS IN THE GIANT SARCOMERIC PROTEIN TITIN ASSOCIATED WITH MUSCLE DISEASE Timir Weston 1 ; Franca Fraternali 2 ;

1 King's College London, London, United Kingdom 2 University College London, London, United Kingdom

Giant modular sarcomeric proteins such as titin have come under increasing scrutiny for their contributions to diseases such as skeletal and cardiac myopathies. Many variants in titin have been linked with these conditions through computational and experimental studies, highlighting that even relatively small, individual missense mutations may have far-reaching structural and functional consequences. However, assessing the impact of all possible single nucleotide variants (SNVs) in titin is complicated by the very large size of this protein. To aid in this task, we have updated the centralised resource for information relating to titin variants, TITINdb2, with newly described pathogenic variants, annotations, structural models, and pathogenicity predictions. By combining these various data together, we can explore the mutational landscape of titin and improve the accuracy of annotation of variant impacts for titin missense variants. We demonstrate the potential of more computationally expensive features, using molecular dynamics, in adding information lacking from simpler representations of these proteins based on sequence and protein structure. We further show how a variant classifier trained on these features improves on the ability to discriminate between neutral and deleterious variants. These offer a first step towards improving our understanding of titin's function and dysfunction in relation to the development of skeletal and cardiac myopathies. Giant modular sarcomeric proteins such as titin have come under increasing scrutiny for their contributions to diseases such as skeletal and cardiac myopathies. Many variants in titin have been linked with these conditions through computational and experimental studies, highlighting that even relatively small, individual missense mutations may have far-reaching structural and functional consequences. However, assessing the impact of all possible single nucleotide variants (SNVs) in titin is complicated by the very large size of this protein. To aid in this task, we have updated the centralised resource for information relating to titin variants, TITINdb2, with newly described pathogenic variants, annotations, structural models, and pathogenicity predictions. By combining these various data together, we can explore the mutational landscape of titin and improve the accuracy of annotation of variant impacts for titin missense variants. We demonstrate the potential of more computationally expensive features, using molecular dynamics, in adding information lacking from simpler representations of these proteins based on sequence and protein structure. We further show how a variant classifier trained on these features improves on the ability to discriminate between neutral and deleterious variants. These offer a first step towards improving our understanding of titin's function and dysfunction in relation to the development of skeletal and cardiac myopathies.

89