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 a few theoretical studies on the fidelity issue. The first model which explicitly considered both sites was proposed in the 1970s and the basic idea was widely accepted by later models. However, all these models did not systematically 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 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.

DNA replication fidelity is a critical issue in molecular biology. Biochemical experiments have provided key insights on the mechanism of fidelity control by DNA polymerases in the past decades, whereas systematic theoretical studies on this issue began only recently. Because of the underlying difficulties of mathematical treatment, comprehensive surveys on the template-specific replication kinetics are still rare. Here we propose a first-passage approach to address this problem, in particular the positional fidelity, for complicated processes with high-order neighbor effects. Under biologically relevant conditions, we derived approximate analytical expressions of the positional fidelity which show intuitively how some key kinetic pathways are coordinated to guarantee the high fidelity, as well as the high velocity, of the replication processes. It is also shown that the fidelity at any template position is dominantly determined by the nearest-neighbor template sequences, which is consistent with the idea that replication mutations are randomly distributed in the genome.

The binding free energy (BFE) of lipid to lipid bilayer is a critical factor to determine the thermal or mechanical stability of the bilayer. Although the molecular structure of lipids has significant impacts on BFE of the lipid, there lacks a systematic study on this issue. In this paper we use coarse-grained molecular dynamics simulation to investigate this problem for several typical phospholipids. We find that both the tail length and tail unsaturation can significantly affect the BFE of lipids but in opposite way, namely, BFE decreases linearly with increasing length, but increases linearly with addition of unsaturated bonds. Inspired by the specific structure of cholesterol which is a crucial component of biomembrane, we also find that introduction of carbo-ring-like structures to the lipid tail or to the bilayer may greatly enhance the stability of the bilayer. Our simulation also shows that temperature can influence the bilayer stability and this effect can be significant when the bilayer undergoes phase transition. These results may be helpful to the design of liposome or other self-assembled lipid systems.

The fidelity of DNA transcription catalyzed by RNA polymerase (RNAP) has long been an important issue in biology. Experiments have revealed that RNAP can incorporate matched nucleotides selectively and proofread the incorporated mismatched nucleotides. However, systematic theoretical researches on RNAP fidelity are still lacking. In the last decade, several theories on RNA transcription have been proposed, but they only handled highly simplified models without considering the high-order neighbor effects and the oligonucleotides cleavage both of which are critical for the overall fidelity. In this paper, we regard RNA transcription as a binary copolymerization process and calculate the transcription fidelity by the steady-state copolymerization theory recently proposed by us for DNA replication. With this theory, the more realistic models considering higher-order neighbor effects, oligonucleotides cleavage, multi-step incorporation and multi-step cleavage can be rigorously handled.

DNA replication is a high-fidelity information-copying processes which is realized by DNA polymerase (DNAP). The high fidelity was explained on the basis of the well-known kinetic-proofreading mechanism (KPR), under which the so-called fidelity-speed trade-off was studied theoretically. However, numerous biochemical experiments have shown that the high fidelity of DNA replication is achieved due to the initial discrimination of polymerase domain of DNAP, as well as the proofreading of the exonuclease domain of DNAP. This exonuclease-proofreading mechanism (EPR) is totally different from KPR. So the trade-off issues are worth being re-examined under EPR. In this paper, we use the first-passage method recently proposed by us to discuss the possible trade-offs in DNA replication under EPR. We show that there could be no fidelity-speed trade-off under EPR, i.e., the fidelity and the speed can be simultaneously enhanced by EPR in a large range of kinetic parameters. This provides a new perspective to understand the experimental data of the exonuclease activity of T7 DNAP and T4 DNAP. We also show that there exists the fidelity-proofreading cost trade-off, i.e., the fidelity is enhanced at the cost of increasing the futile hydrolysis of dNTP. A possible way to avoid this trade-off is to regulate the rate of DNAP translocation: slowing down the forward translocation (in the presence of the terminal mismatch) can enhance the fidelity without changing the speed and the proofreading cost. Our theoretical analysis offers deeper insights on the kinetics-function relation of DNAP. PACS numbers: 82.39.-k, 87.15.Rn, 87.16.A-