P. Shing Ho
ProfessorOffice: MRB 111Phone: 970-491-0569Education: Ph.D., Northwestern UniversityEmail: Shing.Ho@ColoState.eduResearch Title: Nucleic acid structure and function; Biomolecular halogen bonds
The research interests in our laboratory have been focused on the structures and structural gymnastics of nucleic acids and their function, and, more recently, on biomolecular halogen bonds to control molecular structure for bioengineering and ligand binding towards rational drug design. To attack these problems, we apply X-ray crystallography, computational biology, biochemistry, and bioinformatics approaches.
- The exchange of genetic material during recombination, DNA repair, or integration of foreign DNAs involves formation of a four-stranded structure (the Holliday junction), which allows information from one double-helix to exchange with an adjacent duplex. We are currently studying the structural determinants for the formation and stabilization of Holliday junctions in crystals and in solution. Using a unique crystal system that accommodates both B-DNA and A-DNA duplexes and the four-stranded intermediate, we have been able to construct a unique phase map that walks through sequence-conformation space in single-nucleotide steps. This has allowed us to develop models for the role that sequence-dependent formation of the Holliday junction plays in promoting recombination.
- In 1979, a left-handed alternative to Watson and Crick's right-handed double-helical B-DNA model was discovered. This structure (called Z-DNA) has now been implicated in a number of different eukaryotic processes, including RNA editing, coactivation of transcription, and large scale-genomic deletions. We have been mapping the occurrence of Z-DNA across genomes of organisms ranging from eubacteria to archae-bacteria to lower and higher eukaryotes. This phylogenomic analysis has provided us with a map of how and where GC-rich transcriptional elements, including Z-DNA have emerged, and suggest a mechanism for the migration of such elements towards the sites transcriptional initiation through functional evolution. We are now applying this strategy to develop phylogenetic maps to relate organisms based on global functional rather than simple sequence information.
- The A-DNA form was determined by Rosalind Franklin soon after Watson and Crick described the now standard B-DNA structure. This underwound duplex is seen in polymerase active sites and DNA-RNA hybrids. Through a series of 13 single-crystal structures, we mapped the B-DNA to A-DNA transition (B2A-DNA), showing the atomic details how each component of the double-helix contorts as it goes through a series of intermediate steps.
- Epigenetic modifications to DNA are known to affect the structure and function of the genome. We had previously shown that methylation of cytosines can affect the stability of A-DNA, Z-DNA, and Holliday junctions. We are currently studying the effects of 5-hydroxymethylcytosine (recently found to be an important marker in vertebrates) on DNA structure and its role in recombination. In particular, we are interested in how this epigenetic marker is recognized by enzymes, such as endonuclease G, that promote recombination.
Biomolecular Halogen Bonds
- We have recently "rediscovered" a class of molecular interactions (now defined as "halogen bonds" by the IUPAC), which are analogous to the better known hydrogen bond. This interaction is unusual in that covalent halogen complexes (involving chlorine, bromine, or iodine) serve as the electropositive Lewis acid that form stabilizing close-range interactions with electron-rich elements (oxygens, nitrogens, sulfurs, and even the negatively charged phosphate oxygens of nucleic acids). Such interactions are prevalent in protein-ligand interactions, and affect the conformations of DNAs and RNAs. Using the DNA and protein model systems, we have demonstrated that a halogen bond can be engineered to specifically direct the conformation of a macromolecule, and is 2-5 kcal/mol more stable than a comparable hydrogen bond in this environment. We are now applying this interaction as a general tool to engineer molecular structures and for the design of new and more effective inhibitors and drugs.
Awards and Academic Recognition:
- 2018 Scholarship Impact Award, Colorado State University
- Asian Pacific American Cultural Center (APACC) Outstanding Faculty/Staff Award (2018), CSU
- Special Member, Society of Iodine Science, Japan
- Dean's Award, 2014 Art and Science Juried Exhibition, Colorado State University
- Fellow, International Union of Pure & Applied Chemistry (IUPAC)
- Provost N. Preston Davis Award for Innovation in Teaching, Colorado State University
- Fulbright Research Grant, Franco-American Fulbright Commission
- Researcher of the Year (2002), Sigma Xi, Oregon State University
- Discovery Award, Medical Research Foundation of Oregon
- Milton Harris Award for Basic Research, College of Science, Oregon State University
- Wellcome Travel Fellowship
- James A. Shannon Director's Award, NIH
- L. Carter Award for Undergraduate Teaching (student nominated), Oregon State University
- Junior Faculty Research Award, American Cancer Society
- American Cancer Society Postdoctoral Fellowship
- Kodak Gold Key Award in Photography, Juried Exhibit
Anna-Carin C. Carlsson, Matthew R. Scholfield, Rhianon K. Rowe, Melissa Coates Ford, Austin T. Alexander, Ryan A. Mehl, P. Shing Ho (2018) Increasing enzyme stability and activity through hydrogen bond enhanced halogen bonds, Biochemistry, 57: 4135-4147 (DOI: 10.1021/acs.biochem.8b00603, Open Access).
P. Shing Ho, (2017) Halogen bonding in medicinal chemistry: From observations to prediction, Future Medicinal Chemistry, 9(7): 637-640 (PMID 28485645).
Melissa Coates Ford, Matthew Saxton, and P. Shing Ho (2017) Sulfur as an Acceptor to Bromine in Biomolecular Halogen Bonds, J. Phys. Chem. Lett., 8: 4246-4252 (Spotlight highlight, Sept. 7, 2017 issue; PMID: 28796521).
Ho, P.S. (2017) Structure of the Holliday junction: Applications beyond recombination, Biochemical Society Transactions, 45(5): 1149-1158 (Cover article; DOI:10.1042/BST20170048; PMID: 28842529).
Matthew R. Scholfield, Melissa C. Ford, Anna-Carin C. Carlsson, Hawera Butta, Ryan A. Mehl, and P. Shing Ho (2017) Structure-energy relationships of halogen bonds in proteins, Biochemistry, 56(22): 2794-2802. ACS Editor's Choice selection (open access); Viewpoint article; Top 5 most read articles in Biochemistry in 2017.
Rhianon Kay Rowe, and P. Shing Ho (2017) Relationships between halogen and hydrogen bonds in biology, Acta Cryst, B, 73(2): 255-264.
Ford, M. C., and Ho, P.S. (2016) Computational tools to model halogen bonds in medicinal chemistry, Journal of Medicinal Chemistry, 59(5): 1655-1670 (DOI: 10.1021/acs.jmedchem.5b00997). Recognized as "Highly cited" (top 1% cited papers from 2016) by Web of Science.
Scholfield, M. R., Ford, M. C., Vander Zanden, C.M., Billman, M.M., Ho, P. S, and Rappé, A. K., (2015) Force field model of periodic trends in biomolecular halogen bonds, J. Phys Chem, B, 119(29): 9140-9149 (doi: 10.1021/jp509003r)
P. Shing Ho (2014) From Holliday junctions to halogen bonds: How biology informs us about complex chemistry, F&M Scientist, 2: 28 - 54
Vander Zanden, C.M., Carter, M., and Ho, P.S., Direct measurement of thermodynamic parameters from single crystal studies, (2013) Methods, 64: 12 - 18.
Carter, M., Voth, A. R., Scholfield, M., Rummel, B., Sowers, L. C., and Ho, P.S. (2013) Enthalpy-entropy compensation in biomolecular halogen bonds measured in DNA junctions, Biochemistry, 52: 4891-4903.
Desiraju, G.R., Ho, P.S., Kloo, L., Legon, A.C., Marquardt, R., Metrangolo, P., Poloitzer, P.A., Resnati, G., and Rissanen, K. (2013) Definition of the halogen bond, Pure and Applied Chemistry,85(8): 1711-1713. Recognized as "Highly cited" (top 1% cited papers from 2013) by Web of Science.
Scholfield, M.R., Vander Zanden, C.M., Carter, M., and Ho, P.S. (2013) Halogen bonding (X-bonding): A biological perspective, Protein Science, 22: 139-152 (In this issue feature, cover article, PMID: 23225628). Recognized as "Highly cited" (top 1% cited papers from 2013) by Web of Science.
Carter, M., Rappé, A. K., and Ho, P.S. (2012) Scalable anisotropic shape and electrostatic models for biological bromine halogen bonds, J. Chem. Theory Comput, 8: 2461-2473 (cover article).
Maximilliano Vallejos, Pascal Auffinger, & P. Shing Ho, P. S. (2012) “Molecular halogen interactions in biomolecular crystal structures”, Int. Tables Cryst. F., Ch. 23.6.
Megan Carter & P. Shing Ho (2011) Assaying the energies of biological halogen bonds, Crystal Growth & Design, 11: 5087-5095 (cover article).
P. Shing Ho & Megan Carter, 2011, DNA Structure: Alphabet Soup for the Cellular Soul, in DNA Replication (H. Seligmann, ed.), InTech (Open access).
Khuu, P.A., and Ho, P.S., A rare nucleotide base tautomer in the structure of an asymmetric DNA junction, Biochemistry, 2009, 48: 7824-7832, cover article.
Voth, A.R., Khuu, P., Oishi, K., Ho, P. S., (2009) "Halogen bonds as orthogonal molecular interactions to hydrogen bonds", Nature Chemistry, 2009, 1: 74-79. Recognized as "Highly cited" (top 1% cited papers from 2009) by Web of Science.
P. Shing Ho, "Thermogenomics: Thermodynamic-Based Approaches to Genomic Analyses of DNA Structure", Methods, 2008, 47(3): 159-167.
Full, S. J., Deinzer, M. L., Ho, P. S. and Greenwood, J., 2007, Phosphoinositide binding regulates a-actinin CH2 domain structure: Analysis by hydrogen/deuterium exchange mass spectrometry, Protein Sci., v. 16: 2597-2604.
Daniels, M., Hart, L.P., Ho, P.S., Ballini, J.P., Vigny, P., Brochon, J.C.. Intrinsic fluorescence of B and Z forms of poly d(G-m(5)C).poly d(G-m(5)C), a synthetic double-stranded DNA: spectra and lifetimes by the maximum entropy method, Photochem Photobiol Sci. 2007 6: 883-893.
Khuu, P., Sandor, M., DeYoung, J., and Ho, P. S. (2007) "Phylogenomic analysis of the emergence of GC-rich elements", Proc. Natl. Acad. Sci., USA, v. 104, 16528-16533.
Voth, A. R. and Ho, P. S. (2007) "The role of halogen bonding in inhibitor recognition and binding by protein kinases", Curr. Topics Med. Chem., 7: 1336-1348.
Voth, A. R., Franklin A. Hays, F. A. and Ho, P. S. (2007) "Directing macromolecular Conformation through Halogen Bonds", Proc. Natl. Acad. Sci., USA, 104: 6188-6193 (From the cover & In this Issue feature).
Khuu, P., Voth, A. R., Hays, F. A., and Ho, P. S. (2006) "The stacked-X DNA Holliday junction and protein recognition", J. Mol. Recog. 19: 234-242.
Hays, F. A., Schirf, V., Ho, P.S., and Demeler, B. (2006) "Solution formation of Holliday junctions in inverted-repeat sequences", Biochemistry, 45: 2467-2471 (Accelerated Communication, "Hot Article" designation, "Top 20 most accessed papers, 2006").
Hays, F. A., Teegarden, A., Jones, Z. J. R., Harms, M., Raup, D., Watson, J., Cavaliere, E., and Ho, P. S. (2005) "How sequence defines structure: A crystallographic map of DNA structure and conformation", Proc. Natl. Acad. Sci., USA, 102: 7157-7162.
K. E. van Holde, W. C. Johnson, and P. S. Ho (2005) Principles of Physical Biochemistry, 2nd Ed. (Prentice Hall, Upper Saddle River, NJ).