Project Details


Computer simulations will be used to investigate structure/function
relationships in human hemoglobin. The calculations will make use of
modern simulation methods of estimating free energy changes, and
continuum descriptions of some electrostatic interactions, to study the
interaction of hemoglobin with protons and anions, the energetics of
dissociation of tetramers into dimers, and the structural forces
following ligand binding to the T quaternary state. These detailed
investigations are made feasible by recent advances in computing power
and in simulation algorithms, and by corresponding advances in high-
resolution X-ray diffraction studies of mutant and partially liganded
hemoglobins. These developments, plus a large body of evidence collected
over the past decade on the properties of mutant hemoglobins, make
possible a variety of tests of our ability to understand subunit
association and allosteric interactions at an atomic level of detail. Specific interactions to be studied included: (a) binding of protons and
anions to the R and T quaternary states; (b) energetics of tetramer/dimer
dissociation in normal and mutant hemoglobins; (c) structural and
energetic consequences of binding ligands to T state structures; and (d)
properties of the alternate R structure seen in hemoglobin Ypsilanti and
in normal hemoglobin under certain crystallization conditions. The
calculations will make use of solvated molecular dynamics techniques as
well as Poisson-Boltzmann calculations to estimate electrostatic
interactions. In addition to helping to gain an understanding of
structure/function relations in hemoglobin, the project will provide new
insight into the ability of these sorts of theoretical methods to
describe the details of complex protein interactions. Studies on hemoglobin and mutant hemoglobins have important health
implications for several reasons. Modified hemoglobins are currently of
great interest as potential blood substitutes, and successful predictions
of such properties would aid in their design. More generally, hemoglobin
offers an excellent opportunity for basic studies in protein engineering,
since hundreds of mutants have been isolated, and over 60 of these have
already been subjected to extensive physical characterization.
Hemoglobin is also an excellent test case for studies of subunit/subunit
association; such interactions are involved in a great many regulatory
events, and a deeper understanding of the principles involved in protein-
protein recognition could be of major benefit in understanding
biochemical control mechanisms.
Effective start/end date12/1/9311/30/98


  • National Institutes of Health: $177,921.00
  • National Institutes of Health
  • National Institutes of Health: $169,756.00
  • National Institutes of Health


  • Medicine(all)

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