Numerical simulation of aldolase tetramer stability

A theoretical study of aldolase tetramer stability, conducted by finite difference Poisson-Boltzmann (FDPB) and modified Tanford-Kirkwood (MTK) techniques using the atomic coordinates of human aldolase, is described. A method for calculating the interaction energy between subunits is proposed. An analysis of the contribution of different energy terms to the stability and oligomeric equilibria (monomer ⇔ dimer ⇔ tetramer) of aldolase is made. It is shown that the loss of solvation energy and electrostatic interactions at very high and low pH-s destabilise the oligomers. These energy terms are compensated over a wide pH range by the stabilization energy due to hydrophobic interactions. It is shown that the aldolase tetramer is energetically more preferable than other oligomers in the pH range from 5 to 11. Subunit-subunit interactions within the tetramer suggest one dimeric form to be the most stable of the possible sub-parts. For this reason the tetramer can be thought of as a “dimer of dimers”. A comparison between our theoretical results and available experimental data shows that the dissociation of the aldolase tetramer below pH 3–4 cooperatively leads to acid denaturation. A second dissociation is predicted to occur at high pH (>12) in addition to the well known acidic dissociation. The analysis suggests that a mutation of His20 or Arg257 to a neutral residue could decrease the pH of the acidic dissociation by approximately 1 pH unit. Received: 16 February 1998 / Revised version: 8 April 1998 / Accepted: 19 April 1998