Computer simulations of enzyme catalysis: Finding out what has been optimized by evolution

The origin of the catalytic power of enzymes is discussed, paying attention to evolutionary constraints. It is pointed out that enzyme catalysis reflects energy contributions that cannot be determined uniquely by current experimental approaches without augmenting the analysis by computer simulation studies. The use of energy considerations and computer simulations allows one to exclude many of the popular proposals for the way enzymes work. It appears that the standard approaches used by organic chemists to catalyze reactions in solutions are not used by enzymes. This point is illustrated by considering the desolvation hypothesis and showing that it cannot account for a large increase in kcat relative to the corresponding kcage for the reference reaction in a solvent cage. The problems associated with other frequently invoked mechanisms also are outlined. Furthermore, it is pointed out that mutation studies are inconsistent with ground state destabilization mechanisms. After considering factors that were not optimized by evolution, we review computer simulation studies that reproduced the overall catalytic effect of different enzymes. These studies pointed toward electrostatic effects as the most important catalytic contributions. The nature of this electrostatic stabilization mechanism is far from being obvious because the electrostatic interaction between the reacting system and the surrounding area is similar in enzymes and in solution. However, the difference is that enzymes have a preorganized dipolar environment that does not have to pay the reorganization energy for stabilizing the relevant transition states. Apparently, the catalytic power of enzymes is stored in their folding energy in the form of the preorganized polar environment.

Computer-modeling origin of a simple genetic apparatus

This computer simulation is based on a model of the origin of life proposed by H. Kuhn and J. Waser, where the evolution of short molecular strands is assumed to take place in a distinct spatiotemporal structured environment. In their model, the prebiotic situation is strongly simplified to grasp essential features of the evolution of the genetic apparatus without attempts to trace the historic path. With the tool of computer implementation confining to principle aspects and focused on critical features of the model, a deeper understanding of the model's premises is achieved. Each generation consists of three steps: (i) construction of devices (entities exposed to selection) presently available; (ii) selection; and (iii) multiplication of the isolated strands (R oligomers) by complementary copying with occasional variation by copying mismatch. In the beginning, the devices are single strands with random sequences; later, increasingly complex aggregates of strands form devices such as a hairpin-assembler device which develop in favorable cases. A monomers interlink by binding to the hairpin-assembler device, and a translation machinery, called the hairpin-assembler-enzyme device, emerges, which translates the sequence of R1 and R2 monomers in the assembler strand to the sequence of A1 and A2 monomers in the A oligomer, working as an enzyme.

A new class of digital division methods /

"This work was supported in part by the Atomic Energy Commission and the Office of Naval Research under AEC Contract AT(11-1)-415."

Error detection and correction in binary parallel digital computers /

"Retyped October, 1964"

Scheduling and simulation of computation graphs for multiple resource computers /

"UILU Eng 79 1709."

Organization of a very high-speed computer /

"This work was supported in part by the Atomic Energy Commission and the Office of Naval Research under AEC Contract AT(11-1)-415."

Computer design study : access time /

"1-10-1955"

The Illinois pattern recognition computer (Illiac III) /

"Presented at the 18th Annual ACM National Conference, Denver, Colorado August 27, 1963"

The arithmetic subsystem of the new Illinois computer /

"This work was supported in part by the Atomic Energy Commission under Contract No. AT(11-1)-415"

Computer circuits with 30 millimicrosecond operation times /

"February 6, 1957"

Notes on the use of parallelism in ultrahigh speed computer designs /

"December 12, 1955"

Designing computer circuits with a computer /

"This work has been supported by Contract N6ori-71 Task XXIV United States Navy ONR NR 048 094"

Simulation system programming design manual /

"Contract no. N61339-1089."

Demand bibliography : simulation /

"Results from a search of the technical report database ... references cover only unclassified, unlimited document references with abstracts."

A computer program to convert gas analysis data from units of volume percent to molar quantities /

A computer program has been prepared, for use on the ASI-210 digital computer, which will convert gas analysis data from units of volume percent to molar quantities.