Insights on Enzymes and Polymers from Molecular Dynamics Simulations: Applications to Dihydrofolate Reductase Complexes and Starburst Dendrimers

Author: Naylor, Adel Marie

Year: 1989

Degree: Dissertation (Ph.D.)

Advisor: Goddard, William A., III

Committee Members: Baldeschwieler, John D.; Goddard, William A., III; Grubbs, Robert H.; Richards, John H.

Option: Chemistry

DOI: 10.7907/0789-jw44

Abstract

Examples are given for the role of simulation and theory in designing artificial biomimetic and biocatalytic systems. Simulations on the β-alanine starburst dendrimer polymers indicate that, for the higher generation systems: (1) ~50% of the surface area is internal, and (ii) ~50% of the spheroidal volume is solvent- filled. These studies suggest a design for encapsulating and delivering dopamine to the kidney for cardiovascular therapies. Investigations of the penta-erythritol based polyether starburst dendrimers show that: (i) the later generations lack any internal surface area or volume and (ii) the dense-packed limit for these polymers to be the third generation, consistent with experiment. For Dihydrofolate Reductase (DHFR), the modeling and simulations: (i) explain the high degree of kinetic similarity between two dissimilar forms of DHFR; (ii) indicate why site specific mutation (Phe-31→Tyr-31, Leu-54→Ile-54, or Leu-54→Gly-54) causes a significant change in the catalytic rate; and (iii) suggest modifications to engineer E. coli Chicken hybrid proteins capable of reducing folate.

Files