Experiments have shown that two water-soluble fullerene C(60) derivatives, fullerenol and fullerene trimalonic acid, inhibit duplication of DNA via polymerase chain reaction (PCR). It has further been shown that the target of this inhibition is the DNA polymerase protein routinely used in PCR. We have used a combination of molecular docking and molecular dynamics simulations to study the possible DNA polymerase inhibition mechanisms in atomistic detail. The simulations show structural changes in the tip and two alpha helices of a subdomain, crucial for the polymerase activity, upon fullerene derivative binding. Such tertiary structure changes could prevent the binding of DNA to the protein, causing the inhibition of the PCR process. These findings are in agreement with experimental studies, which have shown that the inhibition is not competitive. The proposed mechanism of inhibition would be common for all DNA polymerase proteins, providing new possibilities in antiviral applications of fullerene derivatives.