Medical and Evolution Applications

1. Distinguishing between Neutral and Deleterious Mutants

Most proteins mutants are neutral in their effects.

Stabilities can distinguish some deleterious mutants from neutral ones.  We find neutral mutants in general to have a narrower range of stabilities than deleterious ones.  The deleterious mutants can be either much more or much less stable the neutral ones in general.  See an example below for 98 mutants in 5 different proteins.

The five proteins included were:

2. Annotating Genes of Unknown Function by Improving Protein Sequence Matching

We hypothesize that structural information can help to improve protein sequence matching.  The correlated sequence information for each structural family is collected and the leads to additional biases in possible amino acid substitutions beyond what is being used for independent single amino acid substitutions.  By using a new amino acid substitution matrix that incorporates this information all known cases of where the structures are known to be similar but sequence matches do not indicate any similarity are brought into agreement.  A few examples are shown below:

Details are found in Jia K, Jernigan RL. SeqStruct : A New Amino Acid Similarity Matrix Based on Sequence Correlations and Structural Contacts Yields Sequence-Structure Congruence. bioRxiv 2018, 268904.

This new protein matching approach enables the assignment of function to many proteins (genes) presently having no assigned function.

Funding Organization: 

• NIH
• NSF

Principal Investigator(s): 

• Robert L. Jernigan
• Andrzej Kloczkowski (For Project 1)