Assessing the predicted impact of single amino acid substitutions in calmodulin for CAGI6 challenges.

IF 3.8 2区生物学 Q2 GENETICS & HEREDITY Human Genetics Pub Date : 2024-12-23 DOI:10.1007/s00439-024-02720-y

Paola Turina, Giuditta Dal Cortivo, Carlos A Enriquez Sandoval, Emil Alexov, David B Ascher, Giulia Babbi, Constantina Bakolitsa, Rita Casadio, Piero Fariselli, Lukas Folkman, Akash Kamandula, Panagiotis Katsonis, Dong Li, Olivier Lichtarge, Pier Luigi Martelli, Shailesh Kumar Panday, Douglas E V Pires, Stephanie Portelli, Fabrizio Pucci, Carlos H M Rodrigues, Marianne Rooman, Castrense Savojardo, Martin Schwersensky, Yang Shen, Alexey V Strokach, Yuanfei Sun, Junwoo Woo, Predrag Radivojac, Steven E Brenner, Daniele Dell'Orco, Emidio Capriotti

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Abstract

Recent thermodynamic and functional studies have been conducted to evaluate the impact of amino acid substitutions on Calmodulin (CaM). The Critical Assessment of Genome Interpretation (CAGI) data provider at University of Verona (Italy) measured the melting temperature (T_m) and the percentage of unfolding (%unfold) of a set of CaM variants (CaM challenge dataset). Thermodynamic measurements for the equilibrium unfolding of CaM were obtained by monitoring far-UV Circular Dichroism as a function of temperature. These measurements were used to determine the T_m and the percentage of protein remaining unfolded at the highest temperature. The CaM challenge dataset, comprising a total of 15 single amino acid substitutions, was used to evaluate the effectiveness of computational methods in predicting the T_m and unfolding percentages associated with the variants, and categorizing them as destabilizing or not. For the sixth edition of CAGI, nine independent research groups from four continents (Asia, Australia, Europe, and North America) submitted over 52 sets of predictions, derived from various approaches. In this manuscript, we summarize the results of our assessment to highlight the potential limitations of current algorithms and provide insights into the future development of more accurate prediction tools. By evaluating the thermodynamic stability of CaM variants, this study aims to enhance our understanding of the relationship between amino acid substitutions and protein stability, ultimately contributing to more accurate predictions of the effects of genetic variants.

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评估单氨基酸取代钙调素对cag6挑战的预测影响。

最近进行了热力学和功能研究，以评估氨基酸取代对钙调素（CaM）的影响。维罗纳大学（意大利）的基因组解读关键评估（CAGI）数据提供商测量了一组CaM变体（CaM挑战数据集）的融化温度（Tm）和展开百分比（%展开）。通过监测远紫外圆二色性作为温度的函数，获得了CaM平衡展开的热力学测量。这些测量用于确定Tm和在最高温度下未展开的蛋白质百分比。CaM挑战数据集共包含15个单氨基酸取代，用于评估计算方法在预测与变异相关的Tm和展开百分比以及将其分类为不稳定或不稳定方面的有效性。对于第六版的CAGI，来自四大洲（亚洲、澳大利亚、欧洲和北美）的九个独立研究小组提交了超过52组预测，这些预测来自不同的方法。在本文中，我们总结了我们的评估结果，以突出当前算法的潜在局限性，并为更准确的预测工具的未来发展提供见解。通过对CaM变异的热力学稳定性进行评估，本研究旨在加深我们对氨基酸取代与蛋白质稳定性之间关系的理解，最终有助于更准确地预测遗传变异的影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Human Genetics 生物-遗传学

CiteScore

10.80

自引率

3.80%

发文量

审稿时长

1 months

期刊介绍： Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.