tau P301L - Clarity Protocol

01/3D Structure

📱 For the best experience, view 3D structures on a desktop computer.

? About the 3D Viewer

Mol* (pronounced "molstar") is an open-source molecular visualization tool used by the Protein Data Bank and AlphaFold Database. Learn more at molstar.org.

Controls:

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What am I looking at?

This is a predicted 3D structure of the protein. The ribbon diagram shows the protein backbone—helices appear as coils, sheets as arrows, and loops as simple lines. The shape determines how the protein functions: where it binds to other molecules, how it catalyzes reactions, and how mutations might disrupt its activity.

Color legend:

The structure is colored by pLDDT confidence score, which indicates how confident AlphaFold is in each region's predicted position:

Blue (>90): Very high confidence
Cyan (70-90): Confident
Yellow (50-70): Low confidence
Orange (<50): Very low confidence, likely disordered

02/AI Analysis

TLDR

Tau is a protein that normally helps maintain brain cell structure, but in Alzheimer's disease it becomes damaged and forms toxic tangles. This AlphaFold prediction of the P301L variant (a mutation linked to inherited dementia) shows very low confidence overall, reflecting Tau's naturally floppy, disordered structure that makes it prone to misfolding. The predicted structure reveals that Tau lacks stable 3D shape under normal conditions, which paradoxically enables both its normal function and its dangerous ability to aggregate in disease.

Detailed Analysis

This AlphaFold structure prediction of Tau protein carrying the P301L mutation reveals extremely low confidence metrics, with an average pLDDT of 55.1 and only 19% of residues achieving scores ≥70 (the threshold for reliable structure). These low scores are scientifically informative rather than problematic—they accurately reflect Tau's nature as an intrinsically disordered protein (IDP) that lacks stable three-dimensional structure in solution. Tau normally functions as a microtubule-associated protein, stabilizing the structural scaffolding inside neurons. Its disordered character allows it to bind flexibly to microtubules and respond to cellular regulation. However, this same flexibility makes Tau vulnerable to pathological aggregation. The P301L mutation (proline to leucine at position 301) occurs in a critical region and is associated with inherited frontotemporal dementia and increased Alzheimer's risk. This mutation appears to destabilize Tau's normal interactions and promote its conversion into toxic aggregates that form neurofibrillary tangles, one of the two hallmark pathologies of Alzheimer's disease. The structural prediction shows Tau as an extended, largely unfolded chain throughout its 352 residues, with no sustained regions of high confidence structure. The consistently low pLDDT values across the sequence indicate the protein samples multiple conformations rather than adopting a single stable fold. This ensemble behavior is precisely what enables Tau to transition from its functional, soluble form to pathological aggregates. The P301L variant likely shifts this conformational equilibrium toward aggregation-prone states, though AlphaFold cannot capture this dynamic transition directly. For Alzheimer's research, understanding Tau's structural disorder is crucial because therapeutic strategies must either stabilize its functional conformation or prevent its pathological aggregation. The low-confidence prediction underscores why Tau has been challenging as a drug target—its lack of defined binding pockets and conformational heterogeneity complicate traditional structure-based drug design approaches.

03/AlphaFold Metrics