Distinct missense mutations in a specific gene have been associated with different diseases as well as differing severity of a disease. Current computational methods predict the potential pathogenicity of a missense variant but fail to differentiate between separate disease or severity phenotypes. We have developed a method to overcome this limitation by applying machine learning to features extracted from molecular dynamics simulations, creating a way to predict the effect of novel genetic variants in causing a disease, drug resistance, or another specific trait. As an example, we have applied this novel approach to variants in calmodulin associated with two distinct arrhythmias as well as two different neurodegenerative diseases caused by variants in amyloid-β peptide. The new method successfully predicts the specific disease caused by a gene variant and ranks its severity with more accuracy than existing methods. We call this method molecular dynamics phenotype prediction model.
Calibration of the angular dependence of the amide proton-C alpha proton coupling constants, 3JHN alpha, in a globular protein. Use of 3JHN alpha for identification of helical secondary structure
Solution structure of amyloid beta-peptide(1-40) in a water-micelle environment. Is the membrane-spanning domain where we think it is?
Solution structure of the Alzheimer amyloid beta-peptide (1-42) in an apolar microenvironment. Similarity with a virus fusion domain
Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease
FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death
Differential activation of mitochondrial apoptotic pathways by vasculotropic amyloid-beta variants in cells composing the cerebral vessel walls
Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles
Aβ monomers transiently sample oligomer and fibril-like configurations: ensemble characterization using a combined MD/NMR approach
A mutation in CALM1 encoding calmodulin in familial idiopathic ventricular fibrillation in childhood and adolescence
Designing molecular dynamics simulations to shift populations of the conformational states of calmodulin
Divergent regulation of ryanodine receptor 2 calcium release channels by arrhythmogenic human calmodulin missense mutants
Insights from molecular dynamics simulations: structural basis for the V567D mutation-induced instability of zebrafish alpha-dystroglycan and comparison with the murine model
Solution NMR studies of recombinant Aβ(1-42): from the presence of a micellar entity to residual β-sheet structure in the soluble species
Towards a Unified Theory of Calmodulin Regulation (Calmodulation) of Voltage-Gated Calcium and Sodium Channels
Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies
Monomeric Aβ(1-40) and Aβ(1-42) Peptides in Solution Adopt Very Similar Ramachandran Map Distributions That Closely Resemble Random Coil
Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G
Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes
Molecular dynamics simulations reveal the conformational dynamics of Arabidopsis thaliana BRI1 and BAK1 receptor-like kinases.
Cerebral Amyloid Angiopathy: Diagnosis, Clinical Implications, and Management Strategies in Atrial Fibrillation
Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.
Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.