Don Bashford, PhD
Don Bashford, PhD

Don Bashford, PhD

Associate Member, St. Jude Faculty



BS – Purdue University, W. Lafayette, Indiana (1976)
PhD – Tufts University, Medford, Massachusetts (1985)

Research Interests

We are developing and applying macroscopic dielectric models of the macromolecule-solvent system. The protein is treated as a low dielectric medium immersed in a high dielectric solvent, and the electric potential is determined by the Poisson-Boltzmann equation, which is solved by finite-difference methods. The details of the atomic structure are incorporated into the placement of charges and dielectric boundaries. We call the model, MEAD (Macroscopic Electrostatics with Atomic Detail). MEAD is also the name of our computer program suite, which is is free software that you are welcome to download. The use of the MEAD programs is documented in a README file in the download; and a brief description of the MEAD suite's overall design is given in Bashford, 1997.

A related program is Paul Beroza's mcti (or xmcti), which uses a Monte Carlo method to calculated average protonations of sites, give the intrinsic pKa of each site, and the matrix of site-site interactions. 

The calculation of pKa values is a key test of electrostatic calculations, as well as an important application. We have extended our previous methods of calculating the pKa of ionizable sidechains in proteins by including conformational flexibility of the sidechains (You and Bashford, 1995). The method has been shown to improve the accuracy of our pKa predictions for lysozyme. Further improvements to and applications of this methodology are underway.

We have continued our investigations of the protonation states of functional groups in the light-driven, retinal-containing proton pump, bacteriorhodopsin. Molecular modeling and dynamics simulations were used to build refined models of the ground state structure and models of intermediate states in the photocycle based on two different hypotheses of retinal conformational changes. Our calculations lead to pKa shifts that could promote subsequent proton transfer in the case of one hypotheses, but not the other (Engels et al., 1995).

In collaboration with Professor Robert Van Etten of Purdue University we are calculating pKa values of histidine residues in the wild-type and site-directed mutants of low-molecular-weight protein tyrosine phosphatases. The Van Etten lab has obtained high-resolution X-ray structures of several proteins of this class and found the histidines to have unusually high pKa values. They have also made a number mutants, measured their pKa values, and are working to determine the structures of some of the mutants. Measured and calculated pKa values are presented and compared in Tishmack et el., 1997. More recently, we have made calculations of the highly perturbed protonation states and pKa values in the active site of a a number of different PTPases, in both the free-enzyme, and Michaelis-complex form (paper to appear in J Phys Chem) Together with MEAD, above, you can reproduce the results using the data provided here .

Water strongly modifies inter- and intra- molecular interactions that are important for stability and binding in biological molecules. In particular, water weakens hydrogen bonds and alters the conformational preferences of protein backbone units. We have studied the suitability of MEAD for calculating this effect by comparing MEAD calculations with a number of analogous molecular dynamics calculations of solvation free energies. Good general agreement between the two types of calculations was found (Ösapay et al., 1996). We are also applying a combination of MEAD and molecular dynamics to the study of the conformational preferences of turn-forming peptides.

In collaboration with L. Noodleman and D. Case we have combined density functional theory (DFT) methods of quantum chemistry with the MEAD by using MEAD to calculate the reaction fields due to the solvent or the solvent/protein environment, and DFT to calculate the electronic structure of the solutes. We have applied this method to the calculation of solvation free energies, geometry changes upon solvation, and pKa values of small molecules ( Chen et al., 1994; Richardson et al., 1996 ), and to the redox potentials of iron--sulfur cluster model compounds analogous to protein active sites (Mouesca et al., 1994; Fisher et al., 1996; Li et al., 1996). We have now extended this technique to clusters in protein active sites (manuscript submitted). For this purpose, a three-dielectric version of the MEAD programs has been developed.

Self Assembling Peptide Nanotubes
We are continuing our studies (Engels et al. 1995b) of the diffusion of water and ions through peptide nanotubes of the type developed in the laboratory of M. Reza Ghadiri. The calculations show that water in the nanotubes has a layered structure with deviations that allow water molecules to pass one another, in contrast to the single-file structure of water in the gramicidin pore, which has slower transport properties. We have developed a "hopping model'' of the diffusion process that reproduces the diffusion rates calculated by molecular dynamics and are working on studies of ion diffusion and the effects of altering tube size and composition on transport properties.

Selected Publications

Yun MK, Wu Y, Li Z, Zhao Y, Waddell MB, Ferreira AM, Lee RE, Bashford D, White SW. Catalysis and sulfa drug resistance in dihydropteroate synthase. Science 335(6072):1110-1114, 2012.

Han WG, Sandala GM, Giammona DA, Bashford D, Noodleman L. Mossbauer properties of the diferric cluster and the differential iron(II)-binding affinity of the iron sites in protein R2 of class Ia Escherichia coli ribonucleotide reductase: a DFT/electrostatics study. Dalton Trans 40(42):11164-75, 2011.

Ou L, Ferreira AM, Otieno S, Xiao L, Bashford D, Kriwacki RW. Incomplete folding upon binding mediates Cdk4/cyclin D complex activation by tyrosine phosphorylation of inhibitor p27 protein. J Biol Chem 286(34):30142-51, 2011.

Reed D, Shen Y, Shelat AA, Arnold LA, Ferreira AM, Zhu F, Mills N, Smithson DC, Regni CA,Bashford D, Cicero SA, Schulman BA, Jochemsen AG, Guy RK, Dyer MA. Identification and characterization of the first small molecule inhibitor of MDMX. J Biol Chem 285(14):10786-10796, 2010.

Ferreira AM, Krishnamurthy M, Moore, II, BM, Finkelstein D, Bashford D. Quantitative structure activity relationship (QSAR) for a series of novel cannabinoid derivatives using descriptors derived from semi-empirical quantum chemical calculations. Bioorg Med Chem 2009 (in press).

Mayasundari A, Ferreira AM, He L, Mahindroo N, Bashford D, Fujii N. Rational design of the first small-molecule antagonists of NHERF1/EBP50 PDZ domains. Bioorg Med Chem Lett 18:942-945, 2008.

Toutchkine A, Han W-G, Ullmann M, Liu T, Bashford D, Noodleman L, and Hahn KM. Experimental and DFT studies: Novel structural modifications greatly enhance the solvent sensitivity of live cell imaging dyes. J Phys Chem A 111:10849-10860, 2007.

Lwin TZ, Durant JJ, Bashford D. A fluid salt-bridging cluster and the stabilization of p53. J Mol Bio373:1334-1347, 2007.

Ferreira AA, Bashford D. Model for proton transport coupled to protein conformational change: Application to proton pumping in the bacteriorhodopsin photocycle. J Am Chem Soc 128:16778-16790, 2006.

Sivakolundu SG, Bashford D, Kriwacki RW. Disordered p27Kip1 exhibits intrinsic structure resembling the Cdk2/Cyclin A-bound conformation. J Mol Biol 353:1118-1128, 2005.

Liu T, Han W-G, Himo F, Ullmann GM, Bashford D, Toutchkine A, Hahn K, Noodleman L. Density functional vertical self-consistent reaction field theory for solvatochromism studies of solvent-sensitive dyes. J Phys Chem A 108:3545-3555, 2004.

Bashford D. Macroscopic electrostatic models for protonation states in proteins. Front Biosci 9:1082-1099, 2004.

Onufriev A, Bashford D, Case DA. Exploring protein native states and large-scale conformational changes with a modified generalized born model. Proteins 55(2):383-394, 2004.

Thompson MJ, Bashford D, Noodleman L, Getzoff ED. Photoisomerization and proton transfer in photoactive yellow protein. J Am Chem Soc 125:8186-8194, 2003.

Han WG, Liu T, Himo F, Toutchkine A, Bashford D, Hahn K, Noodleman L. A theoretical study of the {UV}/visible absorption and emission solvatochromic properties of solvent sensitive dyes. Chem Phys Chem 4:1084-1094, 2003.

Onufriev A, Smondyrev A, Bashford D. Proton affinity changes driving unidirectional proton transport in the bacteriorhodopsin photocycle. J Mol Biol 332:1183-1193, 2003.

Beuning PJ, Nagan MC, Cramer CJ, Musier-Forsyth K, Gelp J-L, Bashford D. Efficient aminoacylation of the tRNAAla acceptor stem: Dependence on 2:71 the base pair. RNA 8: 659-670, 2002.

Asthagiri D, Dillet V, Liu T, Noodleman L, Van Etten RL, Bashford D. Density functional study of the mechanism of a tyrosine phosphatase: I. Intermediate formation. J Am Chem Soc 124:10225-10235, 2002.

Onufriev A, Case DA, Bashford D. Effective born radii in the generalized born approximation: The importance of being perfect. J Comp Chem 23:1297-1304, 2002

Asthagiri D, Bashford D. Continuum and atomistic modeling of ion partitioning into a peptide nanotube. Biophys J 82:1176-1189, 2002.

Spassov VZ, Luecke H, Gerwert K, Bashford D. pKa calculations suggest storage of an excess proton in a hydrogen-bonded water network in Bacteriorhodopsin. J Mol Biol 312:203-219, 2001.

Arora N, Bashford D. Solvation energy density occlusion approximation for evaluation of desolvation penalties in biomolecular interactions. Proteins 43:12-27, 2001.

Dillet V, Van Etten RL, Bashford D. Stabilization of charges and protonation states in the active site of the protein tyrosine phosphatases: A compuational study. J Phys ChemB 104:11321-11333, 2000.

Onufriev A, Bashford D, Case DA. Modification of the generalized Born model suitable for macromolecules. J Phys Chem B 104:3712-3720, 2000.

Demchuk E, Genick UK, Woo TT, Getzoff ED, Bashford D. Protonation states and pH-titration in the photocycle of photoactive yellow protein. Biochemistry 39:1100-1113, 2000.

Spassov VZ, Bashford D. Multiple-site ligand binding to flexible macromolecules: Separation of global and local conformational change and an iterative mobile clustering approach. J Comp Chem 20:1091-1111, 1999.

Konecny R, Li J, Fisher CL, Bashford D, Noodleman L. CuZn superoxide dismutase geometry optimization, energetics and redox potential calculations by density functional and electrostatic methods. Inorg Chem 38:940-950, 1999.

Li I, Fisher CL, Konecny R, Dillet V, Bashford D, Noodleman L. Density functional and electrostatic calculations of manganese superoxide dismutase active site complexes in protein environments.Inorg Chem 38:929-939, 1999.

Spassov V, Bashford D. Electrostatic coupling to pH-titrating sites as a source of cooperativity in protein-ligand binding. Protein Science 7:2012-2025, 1998.

Dillet V, Dyson HJ, Bashford D. Calculations of electrostatic interactions and pKas in the active site of Escherichia coli thioredoxin. Biochemistry 37:10298-10306, 1998.

Li J, Nelson MR, Peng CY, Bashford D, Noodleman L. Incorporating protein environments in density functional theory: A self consistent reaction field calculation of redox potentials of [2Fe2S] clusters in ferredoxin and phthalate dioxygenase reductase. J Phys Chem A 102:6311-6324, 1998.

MacKerell AD Jr, et al. All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B 102:3586-3616, 1998.

Tishmack PA, Bashford D, Harms E, Van Etten RL. Use of 1H NMR spectroscopy and computer simulations to analyze histidine pKa changes in a protein tyrosine phosphatase: Experimental and theoretical determination of electrostatic properties in a small protein. Biochemistry 36:11984-11994, 1997.

Last update: March 2012