About the Authors

Donghong Min

Affiliation School of Computational Science, Florida State University, Tallahassee, Florida, United States of America

Helen R Josephine

Affiliation Department of Biochemistry, Brandeis University, Waltham, Massachusetts, United States of America

Hongzhi Li

Affiliation School of Computational Science, Florida State University, Tallahassee, Florida, United States of America

Clemens Lakner

Affiliation Department of Biological Sciences, Florida State University, Tallahassee, Florida, United States of America

Iain S MacPherson

Affiliation Department of Biochemistry, Brandeis University, Waltham, Massachusetts, United States of America

Gavin J. P Naylor

Affiliation Department of Biological Sciences, Florida State University, Tallahassee, Florida, United States of America

David Swofford

Affiliation Department of Biological Sciences, Florida State University, Tallahassee, Florida, United States of America

Lizbeth Hedstrom

To whom correspondence should be addressed. E-mail: hedstrom@brandeis.edu (LH); yang@sb.fsu.edu (WY)

Affiliations Department of Biochemistry, Brandeis University, Waltham, Massachusetts, United States of America , Department of Chemistry, Brandeis University, Waltham, Massachusetts, United States of America

Wei Yang

To whom correspondence should be addressed. E-mail: hedstrom@brandeis.edu (LH); yang@sb.fsu.edu (WY)

Affiliations School of Computational Science, Florida State University, Tallahassee, Florida, United States of America , Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida, United States of America , Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America , College of Life Science, Nankai University, Tianjin 300071, China

Competing Interests

The authors have declared that no competing interests exist.

Author Contributions

DM and HL performed the simulations. HRJ performed and analyzed the pH dependence of the wild-type and mutant IMPDH reactions. ISM performed the complementation experiments. CL, GJPN, and DS performed and analyzed the phylogenetic analysis. LH and WY designed the study and wrote the paper. All authors discussed the results and commented on the paper.