Professional Experiences

• Professor, Eastern Virginia Medical School, 1991-present
• Associate Professor, Eastern Virginia Medical School, 1986-1990
• Adjunct Associate Professor, Old Dominion University, 1986-1990
• Assistant Professor, University of Arizona, 1978-1985
• Scientific Staff, Medical Research Council Cell Biophysics Unit, 1976-1978
• Postdoctoral Fellow, Kings College, University of London, 1973-1976

Education

• Postdoctoral, King's College, London, United Kingdom, 1973-1978
• Ph.D., Brandeis University, Waltham, Mass., 1969-1973
• B.A., University of Colorado, Boulder, Colo., 1964-1969

Research Interests & Funding

A major problem in biophysics and cell biology is to extend our understanding of how the free energy of ATP hydrolysis is coupled to the production of work in muscle and other actomyosin-based contractile systems. There is now strong if not overwhelming evidence that myosin-based movement results largely from a change in lever arm angle while the motor domain is attached to actin, in what is called the tilting level mechanism. What is now required is to understand this mechanism in considerably greater detail, especially the correlation between different biochemical and structural states, details of the movement mechanisms in different myosin types, and whether the tilting mechanism alone provides a complete explanation of movement.

Much of our current work focuses on myosin V. Its 'weakly' bound states with actin have a much higher affinity than those of muscle myosins, allowing study of the pre-power stroke conformation. Moreover, the large size and asymmetry (6 calmodulins in the regulatory domain) make myosinV especially suitable for electron microscopy. Myosin V is expressed in mg quantities using the SF9/baculovirus system which allows the function of the protein to be explored using site-directed mutagenesis. MyosinV has been identified as being the gene responsible for the "dilute mutation" in mice, which has defective transport of pigment to hair follicles, and is also responsible for developmental and neurological disorders.

The primary experimental approach of this laboratory is to use rapid kinetic methods, such as stopped-flow fluorescence, rapid chemical quench, and ms time-resolved cryo electron microscopy (the latter in collaboration with John Trinick's laboratory) to determine the detailed kinetic mechanism of actomyosin ATP hydrolysis in solution and to correlate the biochemical changes with structural changes in the protein.

A recent additional area of research in the laboratory is the mechanism of calcium regulation by the thin filaments in striated muscle. We have recently shown (in a collaboration with Dave Heeley's laboratory) that the principal mechanism of regulation is of the rate conformation change associated with phosphate dissociation from actomyosin-ADP-Pi and that both calcium and rigor myosin bound to the thin filament are required for maximal activation. We are expanding this work to include cardiac muscle thin filament regulation, which is central in the regulation of cardiac contractility.

My laboratory currently has active collaborations with the following laboratories: John Trinick, Leeds University (cryo electron microscopy), Jim Sellers, NIH (myosinV), Leepo Yu, NIH (myosin conformational equilibria), David Heeley, Memorial University (mechanism of thin filament regulation) and Mitsuo Ikebe's laboratory, University of Massachusetts Medical School (myosinVI).

Current Grant Support:

• Cryo Electron-microsopy of Acto-S1 ATPase Intermediates, NIH
• Mechanism of Thin Filament Regulation of Cardiac Actomyosin ATP Hydrolysis, American Heart Association, AHA and NIH

Publications

Heeley DH, Belknap B, White DH. (2006) Maximal activation of skeletal muscle thin filaments requires both rigor myosin S1 and calcium. J Biol Chem. 281(1):668-676

Burton K, White DH, Sleep J. (2005) Kinetics of muscle contraction and actomyosin NTP hydrolysis from rabbit using a series of metal-nucleotide substrates. J Physiol. 563:689-711

Sato O, White HD, Inoue A, Belknap B, Ikebe R, Ikebe M. (2004) Human deafness mutation of mysosin VI (C442Y) accelerates the ADP dissociation rate. J Biol Chem. 279(28):28844-28854

White HD, Thirumurugan K, Walker ML, Trinick J. (2003) A second generation apparatus for time-resolved electron cryo-microscopy using stepper motors and electrospray. J Struct Biol. 144:246-252

Xu S, Offer G, Gu J, White HD, Yu LC. (2003) Temperature and ligand dependence of conformation and helical order in myosin filaments. Biochemistry. 42(2):390-401

Heeley DH, Belknap B, White HD. (2002) Mechanism of regulation of phosphate dissociation from actomyosin-ADP-Pi by thin filament proteins. Proc Natl Acad Sci USA. 99(26):16731-16736

Burgess S, Walker M, Wang F, Sellers JR, White HD, Knight PJ, Trinick J. (2002) The prepower stroke conformation of myosin V. J Cell Biol. 159(6):983-991

Walker M, Zhang XZ, Jiang W, Trinick J, White HD. (1999) Observation of transient disorder during myosin subfragment-1 binding to actin by stopped-flow fluorescence and millisecond time resolution electron cryomicroscopy: evidence that the start of the crossbridge power stroke in muscle has variable geometry. Proc Natl Acad Sci USA. 96(2):465-470

Kambara T, Rhodes TE, Ikebe R, Yamada M, White HD, Ikebe M. (1999) Functional significance of the conserved residues in the flexible hinge region of the myosin motor domain. J Biol Chem. 274(23):16400-16406

Xu S, Gu J, Rhodes T, Belknap B, Rosenbaum G, Offer G, White H, Yu LC. (1999) The M.ADP.P(i) state is required for helical order in the thick filaments of skeletal muscle. Biophys J. 77(5):2665-2676

White HD, Walker ML, Trinick J. (1998) A computer-controlled spraying-freezing apparatus for millisecond time-resolution electron cryomicroscopy. J Struct Biol. 121(3):306-313

Li XD, Rhodes TE, Ikebe R, Kambara T, White HD, Ikebe M. (1998) Effects of mutations in the gamma-phosphate binding site of myosin on its motor function. J Biol Chem. 273(42):27404-27411

White HD, Belknap B, Webb MR. (1997) Kinetics of Nucleoside Triphosphate Cleavage and Phosphate Release Steps by Associated Rabbit Skeletal Actomyosin, Measured Using a Novel Fluorescent Probe for Phosphate. Biochemistry 36:11828-11836

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