Changes in Lysozyme flexibility upon mutation are frequent, large and long-ranged

Search for this publication on Google Scholar
Jacobs, D. J., Verma, D., & Livesay, D. R. (2012). Changes in Lysozyme flexibility upon mutation are frequent, large and long-ranged. Plos Computational Biology.
Download PDF

Analytics

58 views ◎
7 downloads ⇓


Description

Faculty, We investigate changes in human c-type lysozyme flexibility upon mutation via a Distance Constraint Model, which gives a statistical mechanical treatment of network rigidity. Specifically, two dynamical metrics are tracked. Changes in flexibility index quantify differences within backbone flexibility, whereas changes in the cooperativity correlation quantify differences within pairwise mechanical couplings. Regardless of metric, the same general conclusions are drawn. That is, small structural perturbations introduced by single point mutations have a frequent and pronounced affect on lysozyme flexibility that can extend over long distances. Specifically, an appreciable change occurs in backbone flexibility for 48% of the residues, and a change in cooperativity occurs in 42% of residue pairs. The average distance from mutation to a site with a change in flexibility is 17-20 angstrom. Interestingly, the frequency and scale of the changes within single point mutant structures are generally larger than those observed in the hen egg white lysozyme (HEWL) ortholog, which shares 61% sequence identity with human lysozyme. For example, point mutations often lead to substantial flexibility increases within the beta-subdomain, which is consistent with experimental results indicating that it is the nucleation site for amyloid formation. However, beta-subdomain flexibility within the human and HEWL orthologs is more similar despite the lowered sequence identity. These results suggest compensating mutations in HEWL reestablish desired properties.

Details
Title

Changes in Lysozyme flexibility upon mutation are frequent, large and long-ranged

Author(s)

Jacobs, Donald J.
Verma, Deeptak
Livesay, Dennis R.

UNC Charlotte Affiliate Type

Faculty

Extent

1 online resource

Date Created

2012

Genre

articles

Resource Type

text

Abstract

We investigate changes in human c-type lysozyme flexibility upon mutation via a Distance Constraint Model, which gives a statistical mechanical treatment of network rigidity. Specifically, two dynamical metrics are tracked. Changes in flexibility index quantify differences within backbone flexibility, whereas changes in the cooperativity correlation quantify differences within pairwise mechanical couplings. Regardless of metric, the same general conclusions are drawn. That is, small structural perturbations introduced by single point mutations have a frequent and pronounced affect on lysozyme flexibility that can extend over long distances. Specifically, an appreciable change occurs in backbone flexibility for 48% of the residues, and a change in cooperativity occurs in 42% of residue pairs. The average distance from mutation to a site with a change in flexibility is 17-20 angstrom. Interestingly, the frequency and scale of the changes within single point mutant structures are generally larger than those observed in the hen egg white lysozyme (HEWL) ortholog, which shares 61% sequence identity with human lysozyme. For example, point mutations often lead to substantial flexibility increases within the beta-subdomain, which is consistent with experimental results indicating that it is the nucleation site for amyloid formation. However, beta-subdomain flexibility within the human and HEWL orthologs is more similar despite the lowered sequence identity. These results suggest compensating mutations in HEWL reestablish desired properties.

Subjects--Topics

Bioinformatics
Statistics

Is Part Of

PLoS computational biology

Language

English

Publisher's Version

doi:10.1371/journal.pcbi.1002409

Permalink

http://hdl.handle.net/20.500.13093/work:1025

Rights

This item may be protected by copyright and other related rights. Atkins Library provides access to this item for educational and research purposes only; other uses require the permission of the copyright holder.