Protein Folding Problem: A New Approach with Evolutionary Algorithms

Year 2025, Volume: 7 Issue: 2, 80 - 93, 31.08.2025

Peren Jerfi Canatalay , Madina Namazova , Vildan Atalay

https://doi.org/10.46740/alku.1522590

Abstract

AlphaFold is transforming the field of structural biology by predicting three-dimensional (3D) structures from protein sequences. This remarkable achievement has even led to claims that the protein folding problem has been 'solved.' However, the protein folding problem encompasses more than just structure prediction from sequences. Currently, it is unknown whether the AlphaFold revolution will help solve other issues related to protein folding. In this study, we evaluate AlphaFold's ability to predict the impact of single mutations on protein stability (ΔΔG) and function. To explore this question, we subtract the pLDDT and metrics from AlphaFold predictions before and after a single mutation in a protein, correlating the predicted changes with experimentally known ΔΔG values. Additionally, we correlate the same AlphaFold pLDDT metrics with fluorescence levels experimentally tested using a large-scale GFP mutant data set, which indicates the effect of single mutations on the structure. We find very weak or no correlation between AlphaFold output metrics and protein stability or fluorescence change. Our results suggest that AlphaFold may not be immediately applicable to other protein folding problems or applications.

Keywords

Protein Stability , Protein Structure Modeling , Structural Bioinformatics , Ensemble Classifiers , AlphaFold

Protein Katlanmasının Çözülmesi: Evrimsel Algoritmalar ve Yapay Zekanın Gücüyle Yenilikçi Yaklaşımlar

Abstract

AlphaFold, protein dizisinden üç boyutlu (3D) yapı tahmini yaparak yapısal biyoloji alanını değiştirmektedir. Bu olağanüstü başarı, protein katlanma probleminin "çözüldüğü" iddialarına bile yol açmıştır. Ancak protein katlanma problemi, diziden yapı tahmininden daha fazlasını içermektedir. Şu anda, AlphaFold devriminin protein katlanma ile ilgili diğer sorunları çözmeye yardımcı olup olmayacağı bilinmemektedir. Bu çalışmada, AlphaFold'un tekli mutasyonların protein stabilitesi (ΔΔG) ve fonksiyonuna etkisini tahmin etme yeteneğini değerlendiriyoruz. Bu soruyu incelemek için, AlphaFold tahminlerinden pLDDT ve metriklerini bir proteinde tekli mutasyondan önce ve sonra çıkarıyoruz ve tahmin edilen değişikliği deneysel olarak bilinen ΔΔG değerleriyle ilişkilendiriyoruz. Ayrıca, aynı AlphaFold pLDDT metriklerini yapı üzerindeki tekli mutasyonun etkisi ile büyük ölçekli bir GFP mutant veri setini kullanarak deneysel olarak test edilen floresans seviyeleri ile ilişkilendiriyoruz. AlphaFold çıktı metrikleri ile protein stabilitesi veya floresan değişimi arasında çok zayıf veya hiçbir korelasyon bulamıyoruz. Sonuçlarımız, AlphaFold'un diğer protein katlanma problemleri veya uygulamalarına hemen uygulanamayabileceğini göstermektedir.

Keywords

AlphaFold; , Protein Stabilitesi; , Derin Öğrenme; , Şablon Tabanlı Yaklaşımlar , Protein Yapısı Modelleme; , Markov Durum Modelleri

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