AlzDiscovery | APP Outcome

APP (UniProt: P05067)

Amyloid Precursor Protein (APP) could be cleavaged by β-secretase and γ-secretase and produce the β-amyloid (Aβ) peptides with 39-43 amino acids in length, which are the major components of the neuritic plaques¹. APP is strongly associated with the Early-onset AD (EOAD) and familial AD (fAD), and the mutations in APP will result in the increase of the Aβ42/Aβ40 ratio, bringing a stronger neural toxicity².

Mutation Viewer
                                Please choose a missense mutation of interest from the heatmap, and click to get protein structural information. 
                            
Mutation information info_outline
Residue environment info_outline
Mutation effect info_outline
Missense Mutation Selection
                                                
                                                            Result
                                                            Note
                                                        
                                                                    Wild-type
Position
Mutant

                                                                Missense mutations are coordinated by the wild-type amino acid at the bottom (x-axis) and the mutant amino acid on the left (y-axis).
Wild-type positions are based on canonical sequence.

                                                            Prediction
                                                            Predicted phenotypes
                                                        
                                                            Confidence
                                                            
                                                                Predicted probability of the phenotypes, showing how confidence the prediction is.

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Residue Structural Environment
                                                
                                                            Feature
                                                            Explanation
                                                        
                                                            Secondary Structure
                                                            Secondary structure at the mutation site: Helix, Strand, or Loop.
                                                        
                                                            Relative solvent accessibility (RSA)
                                                            
                                                                This feature (range: 0-1) describes how the residue is exposed to solvent.
A residue with a low RSA (e.g. < 20%) is usually located in the buried reigon, while a resiude with a high RSA (e.g. > 20%) is usually more exposed to solvent / closer to the surface.

                                                            Phi & Psi
                                                            Peptide torsion angles of the wild-type residue.
                                                        
                                                            Predicted Local Distance Difference Test (pLDDT)
                                                            
                                                                This feature (range: 0-100) describes how AlphaFold2 is confident with the predicted residue conformation.
Residue with higher pLDDT score is considered as more accurately predicted, while the region with a low pLDDT score (low confidence) is often associated with disorderness. 
pLDDT > 90: Highly confident 
90 > pLDDT > 70: Confident 
70 > pLDDT > 50: Low confident 
50 > pLDDT: Very low confident 
More information: click here

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Mutation Effect
                                                
                                                            Feature
                                                            Explanation
                                                        
                                                            Protein stability
                                                            
                                                                        In-silico biophysical measurement of the change of protein stability (ΔΔG), computed by DDMut open_in_new.
                                                                    
                                                                        We used 0 as a cutoff: 
                                                                    
                                                                        ΔΔG < 0 Kcal/mol means this mutation is destabilising the structure; 
                                                                    
                                                                        ΔΔG > 0 Kcal/mol means this mutation is stabilising the structure;
                                                                    
                                                                        ΔΔG = 0 Kcal/mol refers to netural effect.
                                                                    
                                                            Position-specific substitution 
matrix (PSSM)
                                                            
                                                                Position-specific conservation, computed by PSI-BLAST.
Higher score indicates that this amino acid is more conserved.

                                                            AlphaMissense prediction
                                                            
                                                                Variant effect predictor built on AlphaFold2 open_in_new.
According to AlphaMissense, the cutoffs to classify variants are 0.34 and 0.564.
AlphaMissense_score < 0.34 means this mutation is "likely_benign";
AlphaMissense_score > 0.564 means this mutation is "likely_pathogenic";
AlphaMissense_score in (0.34, 0.564) means this mutation is "ambigious" in phenotypes.

                                                            ESM1b prediction
                                                            
                                                                Prediction of disease variant effects using a deep protein language model open_in_new.
There is no specific cutoff to define pathogenic variants.
But, the smaller the ESM1b_score is, the more likely this variant can be disease-causing. 

                                                            CPT-1 prediction
                                                            
                                                                A cross-protein transfer model to annotate disease variants open_in_new.
There is no specific cutoff to define pathogenic variants.
But, the larger the CPT1_score is, the more likely this variant can be disease-causing. 

                                        Close
                                    
Wild-type :
Position :
Mutant :
Prediction :
Confidence :
Secondary structure :
RSA : 
phi :
psi :
pLDDT :
Protein stability :
PSSM :
AlphaMissense score :
ESM1b score :
CPT-1 score :

NeutralDisease-causing

Result	Note
Wild-type Position Mutant	Missense mutations are coordinated by the wild-type amino acid at the bottom (x-axis) and the mutant amino acid on the left (y-axis). Wild-type positions are based on canonical sequence.
Prediction	Predicted phenotypes
Confidence	Predicted probability of the phenotypes, showing how confidence the prediction is.

Feature	Explanation
Secondary Structure	Secondary structure at the mutation site: Helix, Strand, or Loop.
Relative solvent accessibility (RSA)	This feature (range: 0-1) describes how the residue is exposed to solvent. A residue with a low RSA (e.g. < 20%) is usually located in the buried reigon, while a resiude with a high RSA (e.g. > 20%) is usually more exposed to solvent / closer to the surface.
Phi & Psi	Peptide torsion angles of the wild-type residue.
Predicted Local Distance Difference Test (pLDDT)	This feature (range: 0-100) describes how AlphaFold2 is confident with the predicted residue conformation. Residue with higher pLDDT score is considered as more accurately predicted, while the region with a low pLDDT score (low confidence) is often associated with disorderness. pLDDT > 90: Highly confident 90 > pLDDT > 70: Confident 70 > pLDDT > 50: Low confident 50 > pLDDT: Very low confident More information: click here

Feature	Explanation
Protein stability	In-silico biophysical measurement of the change of protein stability (ΔΔG), computed by DDMut . We used 0 as a cutoff: ΔΔG < 0 Kcal/mol means this mutation is destabilising the structure; ΔΔG > 0 Kcal/mol means this mutation is stabilising the structure; ΔΔG = 0 Kcal/mol refers to netural effect.
Position-specific substitution matrix (PSSM)	Position-specific conservation, computed by PSI-BLAST. Higher score indicates that this amino acid is more conserved.
AlphaMissense prediction	Variant effect predictor built on AlphaFold2 . According to AlphaMissense, the cutoffs to classify variants are 0.34 and 0.564. AlphaMissense_score < 0.34 means this mutation is "likely_benign"; AlphaMissense_score > 0.564 means this mutation is "likely_pathogenic"; AlphaMissense_score in (0.34, 0.564) means this mutation is "ambigious" in phenotypes.
ESM1b prediction	Prediction of disease variant effects using a deep protein language model . There is no specific cutoff to define pathogenic variants. But, the smaller the ESM1b_score is, the more likely this variant can be disease-causing.
CPT-1 prediction	A cross-protein transfer model to annotate disease variants . There is no specific cutoff to define pathogenic variants. But, the larger the CPT1_score is, the more likely this variant can be disease-causing.

Wild-type Structure Viewer

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Representation
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Pathogenicity
AlphaFold2 Confidence
Protein stability ΔΔG
Alanine scanning ΔΔG
Secondary Structure
Residue
Hydrophobicity
Colour Scheme info_outline
Colour scheme
                                                    
                                                        
                                                                Option
                                                                Note
                                                            

                                                        
                                                                Default
                                                                Default colour
                                                            

                                                                Pathogenicity
                                                                Average confidence to Alzheimer's Disease (all possible missense mutations)
                                                            

                                                                AlphaFold2 Confidence
                                                                pLDDT score: how AlphaFold2 is confident with the predicted residue conformation
                                                            

                                                                Protein stability
                                                                Average predicted change of protein stability, computed by DDMut (all possible missense mutations)
                                                            

                                                                Alanine scanning
                                                                Each wild-type amino acid is substituted by an alanine to measure its contribution to the protein stability, computed by DDMut.
                                                            

                                                                Secondary Structure
                                                                Coloured by secondary structure
                                                            

                                                                Residue
                                                                Coloured by residue
                                                            

                                                                Hydrophobicity
                                                                Coloured by hydrophobicity
                                                            

                                                    
                                                

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Option	Note
Default	Default colour
Pathogenicity	Average confidence to Alzheimer's Disease (all possible missense mutations)
AlphaFold2 Confidence	pLDDT score: how AlphaFold2 is confident with the predicted residue conformation
Protein stability	Average predicted change of protein stability, computed by DDMut (all possible missense mutations)
Alanine scanning	Each wild-type amino acid is substituted by an alanine to measure its contribution to the protein stability, computed by DDMut.
Secondary Structure	Coloured by secondary structure
Residue	Coloured by residue
Hydrophobicity	Coloured by hydrophobicity

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Contact types - mutation	Wild-type structure	Mutant structure
Clash
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PI interaction

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Protein Structure

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