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Instruments / Technical Area	Publication Details	Published	Actions
B21-High Throughput SAXS	Dynamic ion pair behavior stabilizes single α-helices in proteins Matthew Batchelor , Marcin Wolny , Emily G. Baker , Emanuele Paci , Arnout P. Kalverda , Michelle Peckham Journal Of Biological Chemistry 294, 3219 - 3234 DOI: 10.1074/jbc.RA118.006752 Diamond Proposal Number(s): [15454] Open Access Show Abstract ▼ Abstract: Ion pairs are key stabilizing interactions between oppositely charged amino acid side chains in proteins. They are often depicted as single conformer salt bridges (hydrogen-bonded ion pairs) in crystal structures, but it is unclear how dynamic they are in solution. Ion pairs are thought to be particularly important in stabilizing single α-helix (SAH) domains in solution. These highly stable domains are rich in charged residues (such as Arg, Lys, and Glu) with potential ion pairs across adjacent turns of the helix. They provide a good model system to investigate how ion pairs can contribute to protein stability. Using NMR spectroscopy, small-angle X-ray light scattering (SAXS), and molecular dynamics simulations, we provide here experimental evidence that ion pairs exist in a SAH in murine myosin 7a (residues 858–935), but that they are not fixed or long lasting. In silico modeling revealed that the ion pairs within this α-helix exhibit dynamic behavior, rapidly forming and breaking and alternating between different partner residues. The low-energy helical state was compatible with a great variety of ion pair combinations. Flexible ion pair formation utilizing a subset of those available at any one time avoided the entropic penalty of fixing side chain conformations, which likely contributed to helix stability overall. These results indicate the dynamic nature of ion pairs in SAHs. More broadly, thermodynamic stability in other proteins is likely to benefit from the dynamic behavior of multi-option solvent-exposed ion pairs.	Mar 2019
I02-Macromolecular Crystallography I04-Macromolecular Crystallography Data acquisition Detectors Diagnostics Health Physics	Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation N. J. Haywood , M. Wolny , B. Rogers , Chi Hung Trinh , Y. Shuping , T. A. Edwards , M. Peckham Biochemical Journal 473, 2485 - 2493 DOI: 10.1042/BCJ20160421 Diamond Proposal Number(s): [6386] Open Access Show Abstract ▼ Abstract: α-actinin 2 (ACTN2) is the only muscle isoform of α-actinin expressed in cardiac muscle. Mutations in this protein have been implicated in mild to moderate forms of hypertrophic cardiomyopathy (HCM). We have investigated the effects of two mutations identified from HCM patients; A119T and G111V, on the secondary and tertiary structure of a purified actin binding domain of ACTN2 by circular dichroism and X-ray crystallography, and show small but distinct changes for both mutations. We also find that both mutants have reduced F-actin binding affinity, although the differences are not significant. The full length mEos2 tagged protein expressed in adult cardiomyocytes shows that both mutations additionally affect Z-disc localisation and dynamic behaviour. Overall, these two mutations have small effects on structure, function and behaviour, which may contribute to a mild phenotype for this disease.	Aug 2016

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