Molecular dynamics simulations for genetic interpretation in protein coding regions: where we are, where to go and when.

Abstract:

:The increasing ease with which massive genetic information can be obtained from patients or healthy individuals has stimulated the development of interpretive bioinformatics tools as aids in clinical practice. Most such tools analyze evolutionary information and simple physical-chemical properties to predict whether replacement of one amino acid residue with another will be tolerated or cause disease. Those approaches achieve up to 80-85% accuracy as binary classifiers (neutral/pathogenic). As such accuracy is insufficient for medical decision to be based on, and it does not appear to be increasing, more precise methods, such as full-atom molecular dynamics (MD) simulations in explicit solvent, are also discussed. Then, to describe the goal of interpreting human genetic variations at large scale through MD simulations, we restrictively refer to all possible protein variants carrying single-amino-acid substitutions arising from single-nucleotide variations as the human variome. We calculate its size and develop a simple model that allows calculating the simulation time needed to have a 0.99 probability of observing unfolding events of any unstable variant. The knowledge of that time enables performing a binary classification of the variants (stable-potentially neutral/unstable-pathogenic). Our model indicates that the human variome cannot be simulated with present computing capabilities. However, if they continue to increase as per Moore's law, it could be simulated (at 65°C) spending only 3 years in the task if we started in 2031. The simulation of individual protein variomes is achievable in short times starting at present. International coordination seems appropriate to embark upon massive MD simulations of protein variants.

journal_name

Brief Bioinform

authors

Galano-Frutos JJ,García-Cebollada H,Sancho J

doi

10.1093/bib/bbz146

subject

Has Abstract

pub_date

2021-01-18 00:00:00

pages

3-19

issue

1

eissn

1467-5463

issn

1477-4054

pii

5669862

journal_volume

22

pub_type

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