Christopher Haydock, Ph.D.

Selected Publications

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Conformational gel analysis and graphics: Measurement of side chain rotational isomer populations by NMR and molecular mechanics

arXiv0706 Gel Analysis and Graphics
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 Figures: 6
 Tables: 0
 References: 21

Christopher Haydock

arXiv:0706.0229v1 [].

Conformational gel analysis and graphics systematically identifies and evaluates plausible alternatives to the side chain conformations found by conventional peptide or protein structure determination methods.  The proposed analysis determines the populations of side chain rotational isomers and the probability distribution of these populations.  The following steps are repeated for each side chain of a peptide or protein: first, extract the local molecular mechanics of side chain rotational isomerization from a single representative global conformation; second, expand the predominant set of rotational isomers to include all probable rotational isomers down to those that constitute just a small percentage of the population; and third, evaluate the constraints vicinal coupling constants and NOESY cross relaxation rates place on rotational isomer populations.  In this article we apply conformational gel analysis to the cobalt glycyl-leucine dipeptide and detail the steps necessary to generalize the analysis to other amino acid side chains in other peptides and proteins.  For a side chain buried within a protein interior, it is noteworthy that the set of probable rotational isomers may contain one or more rotational isomers that are not identified by conventional NMR structure determination methods.  In cases such as this the conformational gel graphics fully accounts for the interplay of molecular mechanics and NMR data constraints on the population estimates.  The analysis is particularly suited to identifying side chain rotational isomers that constitute a small percentage of the population, but nevertheless might be structurally and functionally very significant.

Electron capture decay of indium-111 human carbonic anhydrase I: A time differential K X ray coincidence perturbed angular correlation study

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 Figures: 3
 Tables: 2
 References: 21

Christopher Haydock

In Biophysical Aspects of Auger Processes, AAPM (American Association of Physicists in Medicine) Symposium Proceedings No. 8., Editors R. W. Howell, V. R. Narra, K. S. R. Sastry, and D. V. Rao, (American Institute of Physics, Woodbury, New York, 1992), Pages 106–120, arXiv:physics/0302097v2 [].

The relaxation effects in the perturbed angular correlation spectra of ¹¹¹In human carbonic anhydrase I (HCA I) are the result of chemical transmutation and/or the complex Auger cascades that follow the electron capture decay of ¹¹¹In.  Time differential K X ray coincidence perturbed angular correlation (PAC) spectroscopy shows that these relaxation effects are independent of the Auger cascade intensity.  This suggests that chemical transmutation is responsible for the relaxation effects, and that bond breaking and damage product formation around the decay site resulting from localized energy deposition by Auger and Coster-Kronig electrons probably occur in the microsecond time regime.  Numerical simulations of chemical transmutation relaxation effects in the time differential PAC spectrum of ¹¹¹In HCA I are also presented.

Protein side chain rotational isomerization: A minimum perturbation mapping study

JCP Minimum Perturbation Mapping
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 Figures: 6  (vector graphics)
 Tables: 3
 References: 47

Christopher Haydock

Journal of Chemical Physics, Volume 98, Number 10, May 15, 1993, Pages 8199–8214, DOI:10.1063/1.464525.

A theory of the rotational isomerization of the indole side chain of tryptophan-47 of variant-3 scorpion neurotoxin is presented.  The isomerization potential energy, entropic part of the isomerization free energy, isomer probabilities, transition state theory reaction rates, and indole order parameters are calculated from a minimum perturbation mapping over tryptophan-47 χ¹ × χ² torsion space.  A new method for calculating the fluorescence anisotropy from molecular dynamics simulations is proposed.  The method is based on an expansion that separates transition dipole orientation from chromophore dynamics.  The minimum perturbation potential energy map is inverted and applied as a bias potential for a 100 ns umbrella sampling simulation.  The entropic part of the isomerization free energy as calculated by minimum perturbation mapping and umbrella sampling are in fairly close agreement.  Throughout, the approximation is made that two glutamine and three tyrosine side chains neighboring tryptophan-47 are truncated at the Cᵝ atom.  Comparison with the previous combination thermodynamic perturbation and umbrella sampling study suggests that this truncated neighbor side chain approximation leads to at least a qualitatively correct theory of tryptophan-47 rotational isomerization in the wild type variant-3 scorpion neurotoxin.  Analysis of van der Waals interactions in a transition state region indicates that for the simulation of barrier crossing trajectories a linear combination of three specially defined dihedral angles will be superior to a simple side chain dihedral reaction coordinate.

Design of ribonuclease T1 mutants with tryptophan-59 in noncrystallographic conformations

SPIE 1994 Design
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 Figures: 1
 References: 4

Christopher Haydock

In Time-Resolved Laser Spectroscopy in Biochemistry IV, SPIE (Society of Photo-Optical Instrumentation Engineers) Proceedings, Volume 2137, 1994, Pages 127–128, DOI:10.1117/12.182717

Minimum perturbation mapping reveals that five side chain conformations of tryptophan-59 can potentially pack in the hydrophobic core of ribonuclease T1.  In the crystallographic structure tryptophan-59 is in the trans perpendicular conformation.  The other four wells in the tryptophan-59 χ¹ × χ² torsion space minimum perturbation mapping are trans antiperpendicular, gauche⁺ antiperpendicular, gauche⁺ perpendicular, and gauche⁻ perpendicular.  The point mutations V33I and V33L are predicted to stabilize the trans antiperpendicular over the perpendicular conformation by 1.3 and 0.6 kcal/mol, respectively.  The three gauche conformations require the creation of a new pocket within the protein core.  The Mutation F80G creates the pocket for the gauche⁺ antiperpendicular tryptophan-59 conformation.  The additional mutation V78A makes a more generous pocket for this conformation.  The three mutations A19G, V78G and F80L create the pocket for the gauche⁺ perpendicular conformation.  A slightly more generous mutation at residue 80 may be required to fully stabilize this conformation.  It does not appear possible to create a pocket that fits the gauche⁻ perpendicular conformation better than the other two gauche conformations.  The expression of ribonuclease-T1 mutants with tryptophan-59 in a gauche conformation probably requires filling in the crystallographic tryptophan-59 pocket.  The mutations A22F, V33F, or V67F are all promising possibilities for this purpose.

Two-way packing model for ribonuclease T1 fluorescence

SPIE 1994 Two-way packing
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 Figures: 3
 Tables: 2
 References: 6

Christopher Haydock, Salah S. Sedarous, Franklyn G. Prendergast, and Teresa A. Felmlee

In Time-Resolved Laser Spectroscopy in Biochemistry IV, SPIE (Society of Photo-Optical Instrumentation Engineers) Proceedings, Volume 2137, 1994, Pages 179–184, DOI:10.1117/12.182724.

The fluorescence intensity decay of ribonuclease T1 is biexponential at neutral pH.  The lifetimes in nanoseconds and preexponential factors of the exponential components are 3.9 (81%) and 1.7 (19%).  The mutations A22L, G23A, L26A, V67G, and V67D, which all neighbor tryptophan-59, have a fairly small effect on this biexponential decay.  The lifetime of the long lived component varies from 3.7 to 4.2 nanoseconds and the preexponential varies from 75% to 92%.  The emission maximum varies from 319 to 328 nm and the acrylamide quenching rate constant varies from 2.0 to 4.0 × 10⁸ M⁻¹s⁻¹ for these mutations.  Minimum perturbation mapping simulations of the tryptophan-59 side chain in wild type ribonuclease T1 show that the χ² side chain dihedral angle may adopt either a perpendicular or an antiperpendicular conformation.  These computational and spectroscopic results lead us to propose a two-way packing model for tryptophan-59.  This model predicts the relative free energies of the perpendicular and antiperpendicular conformations and acrylamide interaction site to indole ring distances for the wild type and mutant ribonucleases.

Thallium-201: An experimental and a theoretical radiobiological approach to dosimetry

JNM 1983 Kassis Tl201
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 Figures: 7
 Tables: 7
 References: 41

Amin I. Kassis, S. James Adelstein, Christopher Haydock, Kandula S. R. Sastry

Journal of Nuclear Medicine, Volume 24, 1983, Pages 1164–1175, PMID: 6644377 [PubMed - indexed for MEDLINE].

The kinetics of uptake and retention of Tl-201, Rb-86, K-42, and K-43 have been studied in cultured mammalian cells and related to their radiotoxicities.  Among the four radionuclides, the intracellular localization of Tl-201, the only emitter of Auger electrons, was important for the manifestation of its cytocidal effects.  The results have been found consistent with the short-range nature of Auger electrons and are substantiated by our theoretical dosimetric calculations.  The possible implications of this in vitro system for applications of Tl-201 in nuclear medicine are indicated.