Protein ensembles link genotype to phenotype

Ruth Nussinov*, Chung Jung Tsai, Hyunbum Jang

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

53 Scopus citations


Classically, phenotype is what is observed, and genotype is the genetic makeup. Statistical studies aim to project phenotypic likelihoods of genotypic patterns. The traditional geno-type-to-phenotype theory embraces the view that the encoded protein shape together with gene expression level largely determines the resulting phenotypic trait. Here, we point out that the molecular biology revolution at the turn of the century explained that the gene encodes not one but ensembles of conformations, which in turn spell all possible gene-asso-ciated phenotypes. The significance of a dynamic ensemble view is in understanding the linkage between genetic change and the gained observable physical or biochemical characteristics. Thus, despite the transformative shift in our understanding of the basis of protein structure and function, the literature still commonly relates to the classical genotype–phenotype paradigm. This is important because an ensemble view clarifies how even seemingly small genetic alterations can lead to pleiotropic traits in adaptive evolution and in disease, why cellular pathways can be modified in monogenic and polygenic traits, and how the environment may tweak protein function.

Original languageEnglish
Article numbere1006648
JournalPLoS Computational Biology
Issue number6
StatePublished - Jun 2019


FundersFunder number
National Institutes of HealthHHSN261200800001E
National Cancer InstituteZIABC010440


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