How do enzymes do this? The answer is surprisingly complicated. Let's look at a simple reaction forming part of the glycolysis pathway.
In this reaction, one molecule of DHAP is converted to one molecule of G3P, and vice versa (the reaction is readily reversible). The reaction is catalyzed by a famous enzyme called triose phosphate isomerase or TPI.
As the reaction proceeds, there will be a point when neither DHAP or G3P exist. Instead, there will be a transition state whose structure is somewhere in between that of the product and the substrate. This transition state only exists for a nanosecond or less. One of the things that enzymes do is to create a pocket where the binding of the transition state intermediate1 is favored. What this does is to lower the activation energy between the reactant and product making the transition from one to the other much easier. The net effect is to speed up the process by many order of magnitude.
Transition state stabilization is one of the most important mechanisms of enzyme catalysis. There are very few direct proofs of this in the scientific literature because the hypothetical transition state is so unstable and transient. However, there is a huge number of indirect experiments that confirm the importance of this mechanism. They include the binding of more stable transition state analogues and the modeling of hypothetical transition states into the active site of an enzyme.
Another important mechanism of catalysis is substrate binding. The role of an enzyme is to recruit reactants such as DHAP into the active site of the enzyme where it is precisely positioned for the subsequent reaction. In the example show here, the reactant has bound to the active site of trisose phosphate isomerase where it aligned with two important amino acid side chains: histidine (His, dark blue) and glutamate (Glu, red). In this case, a single reactant is oriented correctly for the subsequent reaction. In other cases the role of binding is more obvious since two different reactions are correctly positioned to react with each other.
The enzyme serves as a stable platform for aligning the substrates in the correct orientation. The arrangement of the active site pocket and the surrounding channel can greatly increase the probability that the reaction will take place. In solution, without enzyme, many collisions between molecules will be nonproductive.
In addition to transition state stabilization, and substrate binding effects, enzymes also exhibit catalytic effects on acceleration of reactions. There are many different kinds of catalytic effects but the main ones are ionization effects, acid-base catalysis, and covalent catalysis. In all cases, the effect is mediated by the side chains of amino acid at the active site.
An example of acid-base catalysis in triose phosphate isomerase is shown in the diagram on the right. You don't need to follow the specifics of the reaction. The idea is that a histidine side chain (His-95) forms a hydrogen bond with the substrate while a glutamate residue (Glu-165) acts as an acid-base catalyst to extract a proton from DHAP.
The role of amino acid side chains in catalysis and substrate binding was mostly worked out the 1970's when the first enzyme structures were being solved. One of the first examples was ribonuclease A [Monday's Molecule #75]. Stanford Moore and William Stein received the Nobel Prize in 1972 for being among the very first biochemists to demonstrate how enzyme work at the molecular level.
1. A transition state is not an intermediate. The difference is too technical for this posting. I just want to make sure we don't get any quibbles in the comments section.