Matthew Hj Cordes
Associate Professor, BIO5 Institute
Associate Professor, Chemistry and Biochemistry-Sci
Primary Department
Department Affiliations
(520) 626-1175
Research Interest
Matthew Cordes, Ph.D. is an Associate Professor of Chemistry and Biochemistry at the University of Arizona College of Science. Dr. Cordes’ research focuses on the origin and evolution of new protein structures and functions. He has published approximately 30 original research papers and presents his work frequently at national meetings such as the Protein Society and Gordon Research Conferences on Proteins and Biopolymers. Dr. Cordes’ primary research contributions are in four fields of protein evolution. First, his laboratory has identified cases in which a new type of protein structure has evolved from a preexisting structure. Second, he has identified evolutionary codes by which proteins that bind specific sites on double-stranded DNA evolve to recognize new target sites. Third, he studies the evolution of proteins in bloodsucking insects and spiders that affect blood homeostasis or cause dermonecrotic effects in mammalian tissue. Finally, he uses bioinformatics to identify hidden patterns in protein sequences that allow them to fold correctly and avoid aggregation such as that which occurs in Alzheimer’s disease. Dr. Cordes presently holds a BIO5 pilot project seed grant to study the evolution of enzyme toxins in brown spider venom.

Publications

Hall, B. M., Vaughn, E. E., Begaye, A. R., & Cordes, M. H. (2011). Reengineering Cro protein functional specificity with an evolutionary code. Journal of Molecular Biology, 413(5).

Cro proteins from different lambdoid bacteriophages are extremely variable in their target consensus DNA sequences and constitute an excellent model for evolution of transcription factor specificity. We experimentally tested a bioinformatically derived evolutionary code relating switches between pairs of amino acids at three recognition helix sites in Cro proteins to switches between pairs of nucleotide bases in the cognate consensus DNA half-sites. We generated all eight possible code variants of bacteriophage λ Cro and used electrophoretic mobility shift assays to compare binding of each variant to its own putative cognate site and to the wild-type cognate site; we also tested the wild-type protein against all eight DNA sites. Each code variant showed stronger binding to its putative cognate site than to the wild-type site, except some variants containing proline at position 27; each also bound its cognate site better than wild-type Cro bound the same site. Most code variants, however, displayed poorer affinity and specificity than wild-type λ Cro. Fluorescence anisotropy assays on λ Cro and the triple code variant (PSQ) against the two cognate sites confirmed the switch in specificity and showed larger apparent effects on binding affinity and specificity. Bacterial one-hybrid assays of λ Cro and PSQ against libraries of sequences with a single randomized half-site showed the expected switches in specificity at two of three coded positions and no clear switches in specificity at noncoded positions. With a few caveats, these results confirm that the proposed Cro evolutionary code can be used to reengineer Cro specificity.

Cordes, M. H., Davidson, A. R., & Sauer, R. T. (1996). Sequence space, folding and protein design. Current Opinion in Structural Biology, 6(1), 3-10.

PMID: 8696970;Abstract:

Protein design efforts are beginning to yield molecules with many of the properties of natural proteins. Such experiments are informed by and contribute to our understanding of the sequence determinants of protein folding and stability. The most important design elements seem to be the proper placement of hydrophobic residues along the polypeptide chain and the ability of these residues to form a well packed core. Buried polar interactions, turn and capping motifs and secondary structural propensities also contribute, although probably to a lesser extent.

Bull, H. G., Thornberry, N. A., Cordes, M. H., & Patchett, A. A. (1985). Inhibition of rabbit lung angiotensin-converting enzyme by N(α)-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline and N(α)-[(S)-1-carboxy-3-phenylpropyl]L-lysyl-L-proline. Journal of Biological Chemistry, 260(5), 2952-2962.

PMID: 2982845;Abstract:

Two novel peptide analogs, N(α)-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline and the corresponding L-lysyl-L-proline derivative, have been demonstrated to be potent competitive inhibitors of purified rabbit lung angiotensin-converting enzyme: K(i) = 2 and 1 x 10-10 M, respectively, at pH 7.5, 25°C, and 0.3 M chloride ion. Second-order rate constants for addition of these inhibitors to enzyme under the same conditions are in the range 1-2 x 106 M-1 s-1; first-order rate constants for dissociation of the EI complexes are in the range 1-4 x 10-4 s-1. The association rate constants are similar to those measured for D-3-mercapto-2-methylpropanoyl-L-proline, captopril, but the dissociation rate constants are severalfold slower and account for the higher affinity of these inhibitors for the enzyme. The dissociation constant for the EI complex containing N(α)-[(S)-1-carboxy-3-phenylpropyl]L-alanyl-L-proline is pH-dependent, and reaches a minimum at approximately pH 6: K(i) = 4 ± 1 x 10-11 M. The pH dependence is consistent either with a model for which the protonation state of the secondary nitrogen atom in the inhibitor determines binding affinity, or one for which ionizations on the enzyme alone influence affinity for these inhibitors. The affinity of this inhibitor for the zinc-free apoenzyme is 2 x 104 times less than that for the holoenzyme. If considered as a 'collected product' inhibitor, N(α)-[(S)-1-carboxy-3-phenylprolyl]L-alanyl-L-proline appears to derive an additional factor of 375 M in its affinity for the enzyme compared to that of the two products of its hypothetical hydrolysis, a consequence of favorably entropy effects.

Bouvignies, G., Korzhnev, D. M., Neudecker, P., Hansen, D. F., H., M., & Kay, L. E. (2010). A simple method for measuring signs of 1HN chemical shift differences between ground and excited protein states. Journal of Biomolecular NMR, 47(2), 135-141.

PMID: 20428928;PMCID: PMC3034452;Abstract:

NMR relaxation dispersion spectroscopy is a powerful method for studying protein conformational dynamics whereby visible, ground and invisible, excited conformers interconvert on the millisecond time-scale. In addition to providing kinetics and thermodynamics parameters of the exchange process, the CPMG dispersion experiment also allows extraction of the absolute values of the chemical shift differences between interconverting states, |δω̄|, opening the way for structure determination of excited state conformers. Central to the goal of structural analysis is the availability of the chemical shifts of the excited state that can only be obtained once the signs of δω̄ are known. Herein we describe a very simple method for determining the signs of 1HN δω̄ values based on a comparison of peak positions in the directly detected dimensions of a pair of 1HN-15N correlation maps recorded at different static magnetic fields. The utility of the approach is demonstrated for three proteins that undergo millisecond time-scale conformational rearrangements. Although the method provides fewer signs than previously published techniques it does have a number of strengths: (1) Data sets needed for analysis are typically available from other experiments, such as those required for measuring signs of 15N δω̄ values, thus requiring no additional experimental time, (2) acquisition times in the critical detection dimension can be as long as necessary and (3) the signs obtained can be used to cross-validate those from other approaches. © Springer Science+Business Media B.V. 2010.

LeFevre, K. R., & Cordes, M. H. (2003). Retroevolution of lambda Cro toward a stable monomer. Proceedings of the National Academy of Sciences of the United States of America, 100(5).

The Cro protein from bacteriophage lambda has a dimeric alpha+beta fold that evolved from an ancestral all-alpha monomer. The sequence mutations responsible for this dramatic structural evolution are unknown. Here we use analysis of sequence alignments to show that Ala-33, a small side chain in the hydrophobic "ball-and-socket" dimer interface of lambda Cro, was a much larger tryptophan side chain at a previous point in evolution. The retroevolutionary lambda Cro-A33W mutant shows a 10-fold reduction in dimerization affinity relative to the wild type as well as a large increase in monomer thermal stability (Delta T(m) > 10 degrees C), apparently due to partial filling of the hydrophobic socket from within the same monomer. An additional mutation in the dimer interface, F58D, almost completely abolishes detectable dimerization while maintaining the high monomer stability. The secondary structure content of the monomerized versions of lambda Cro is similar to that of the wild-type protein, and the tertiary structure of the monomer appears relatively well defined. These results (i) support a model in which the ball-and-socket dimer interface of lambda Cro was created by altered volume mutations within a limited branch of the Cro lineage and (ii) suggest the possibility that the evolution of the alpha+beta dimer from an all-alpha monomer proceeded through an alpha+beta monomer intermediate.