  The fidelity of DNA replication by DNA polymerase (DNAP) has long been an
important issue in biology. While numerous experiments have revealed details of
the molecular structure and working mechanism of DNAP which consists of both a
polymerase site and an exonuclease (proofreading) site, there were quite few
theoretical studies on the fidelity issue. The first model which explicitly
considered both sites was proposed in 1970s' and the basic idea was widely
accepted by later models. However, all these models did not systematically and
rigorously investigate the dominant factor on DNAP fidelity, i.e, the
higher-order terminal effects through which the polymerization pathway and the
proofreading pathway coordinate to achieve high fidelity. In this paper, we
propose a new and comprehensive kinetic model of DNAP based on some recent
experimental observations, which includes previous models as special cases. We
present a rigorous and unified treatment of the corresponding steady-state
kinetic equations of any-order terminal effects, and derive analytical
expressions for fidelity in terms of kinetic parameters under bio-relevant
conditions. These expressions offer new insights on how the the higher-order
terminal effects contribute substantially to the fidelity in an order-by-order
way, and also show that the polymerization-and-proofreading mechanism is
dominated only by very few key parameters. We then apply these results to
calculate the fidelity of some real DNAPs, which are in good agreements with
previous intuitive estimates given by experimentalists.
