Leveraging Sequence Purification for Accurate Prediction of Multiple Conformational States with AlphaFold2.

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Tác giả: Xiaolin Cheng, Shen Wang, Enming Xing, Junjie Zhang

Ngôn ngữ: eng

Ký hiệu phân loại: 133.5266 Astrology

Thông tin xuất bản: United States : Research square , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 723382

AlphaFold2 (AF2) has transformed protein structure prediction by harnessing co-evolutionary constraints embedded in multiple sequence alignments (MSAs). MSAs not only encode static structural information, but also hold critical details about protein dynamics, which underpin biological functions. However, these subtle coevolutionary signatures, which dictate conformational state preferences, are often obscured by noise within MSA data and thus remain challenging to decipher. Here, we introduce AF-ClaSeq, a systematic framework that isolates these co-evolutionary signals through sequence purification and iterative enrichment. By extracting sequence subsets that preferentially encode distinct structural states, AF-ClaSeq enables high-confidence predictions of alternative conformations. Our findings reveal that the successful sampling of alternative states depends not on MSA depth but on sequence purity. Intriguingly, purified sequences encoding specific structural states are distributed across phylogenetic clades and superfamilies, rather than confined to specific lineages. Expanding upon AF2's transformative capabilities, AF-ClaSeq provides a powerful approach for uncovering hidden structural plasticity, advancing allosteric protein and drug design, and facilitating dynamics-based protein function annotation.
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