A detailed analysis of the stability and flipping dynamics of a delayed exclusive toggle switch is performed. We use forward flux sampling method combined with delayed stochastic simulation algorithm to get the statio...A detailed analysis of the stability and flipping dynamics of a delayed exclusive toggle switch is performed. We use forward flux sampling method combined with delayed stochastic simulation algorithm to get the stationary distribution function, the switching rate, and path- ways, as well as the transition state ensemble. Interestingly, under the influence of time delay, the stationary distribution corresponding to the stable states become narrower and the population in the transition region is significantly enhanced. In addition, the flipping rate increases monotonically with delay. Such findings demonstrate that time delay could reduce the stability of the bistable genetic switch dramatically. Furthermore, the transition pathways, characterized by the difference in the protein numbers and the state of operator, show larger discrepancy between the forward and backward switching process with increas- ing delay, indicating that transcriptional and translational delay can remarkably affect the flipping dynamics. Specifically, for the transition state, the difference in the probability of finding the operator site bound by the two different protein dimers is enlarged by delay, which further illustrates the crucial role of time delay on the stability and switching dynamics of genetic toggle switches.展开更多
Agonist binding of A2A adenosine receptor （A2AAR） shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing A2AAR selectively binding agonist...Agonist binding of A2A adenosine receptor （A2AAR） shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing A2AAR selectively binding agonists. Using molecular dynamics （MD） simula- tions, we have studied the interactions between A2AAR and its agonist （adenosine）, and analyzed the induced dynamic behaviors of the receptor. Key residues interacting with adenosine are identified： A63^2.61,I66^2.64,V84^3.32,L85^3.33,T88^3.36,F168^5.29,M177^5.38,L249^6.51,H250^6.52 and N253^6.55 interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L167^5.28 is observed, which supports our previous findings that L1675^5.28 is an antagonist specific binding reside. The dynamic be- haviors of agonist bound A2AAR are found to be different from apo-A2AAR in three typical functional switches： （i） tight ＂ionic lock＂ forms in adenosine-A2AAR, but it is in equilibrium between formation and breakage in apo-A2AAR; （ii） the ＂rotamer toggle switch＂, T88^3.36/F242^6.44/W246^6.48, adopted different rotameric conformations in adenosin-A2AAR and apo-A2AAR; （iii） adenosine-A2AAR has a flexible intracellular loop 2 （IC2） and s-helical IC3, while apo-A2AAR preferred s-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic functional switches in adenosine-A2AAR and apo-A2AAR.展开更多
Taking the famous genetic toggle switch as an example,we numerically investigated the effect of noise on bistability.We found that extrinsic noise resulting from stochastic fluctuations in synthesis and degradation ra...Taking the famous genetic toggle switch as an example,we numerically investigated the effect of noise on bistability.We found that extrinsic noise resulting from stochastic fluctuations in synthesis and degradation rates and from the environmental fluctuation in gene regulatory processes can induce coherent switch,and that there is an optimal noise intensity such that the noise not only can induce this switch,but also can amplify a weak input signal.In addition,we found that the intrinsic noise introduced through the Poisson τ-leap algorithm cannot induce such a switch.展开更多
基金the National Basic Research Program of China，the National Natural Science Foundation of China，the Fundamental Research Funds for the Central Universities
文摘A detailed analysis of the stability and flipping dynamics of a delayed exclusive toggle switch is performed. We use forward flux sampling method combined with delayed stochastic simulation algorithm to get the stationary distribution function, the switching rate, and path- ways, as well as the transition state ensemble. Interestingly, under the influence of time delay, the stationary distribution corresponding to the stable states become narrower and the population in the transition region is significantly enhanced. In addition, the flipping rate increases monotonically with delay. Such findings demonstrate that time delay could reduce the stability of the bistable genetic switch dramatically. Furthermore, the transition pathways, characterized by the difference in the protein numbers and the state of operator, show larger discrepancy between the forward and backward switching process with increas- ing delay, indicating that transcriptional and translational delay can remarkably affect the flipping dynamics. Specifically, for the transition state, the difference in the probability of finding the operator site bound by the two different protein dimers is enlarged by delay, which further illustrates the crucial role of time delay on the stability and switching dynamics of genetic toggle switches.
文摘Agonist binding of A2A adenosine receptor （A2AAR） shows protective effects against inflammatory and immune. Efforts are exerted in understanding the general mechanism and developing A2AAR selectively binding agonists. Using molecular dynamics （MD） simula- tions, we have studied the interactions between A2AAR and its agonist （adenosine）, and analyzed the induced dynamic behaviors of the receptor. Key residues interacting with adenosine are identified： A63^2.61,I66^2.64,V84^3.32,L85^3.33,T88^3.36,F168^5.29,M177^5.38,L249^6.51,H250^6.52 and N253^6.55 interacting with adenosine with affinities larger than 0.5 kcal/mol. Moreover, no interaction between adenosine and L167^5.28 is observed, which supports our previous findings that L1675^5.28 is an antagonist specific binding reside. The dynamic be- haviors of agonist bound A2AAR are found to be different from apo-A2AAR in three typical functional switches： （i） tight ＂ionic lock＂ forms in adenosine-A2AAR, but it is in equilibrium between formation and breakage in apo-A2AAR; （ii） the ＂rotamer toggle switch＂, T88^3.36/F242^6.44/W246^6.48, adopted different rotameric conformations in adenosin-A2AAR and apo-A2AAR; （iii） adenosine-A2AAR has a flexible intracellular loop 2 （IC2） and s-helical IC3, while apo-A2AAR preferred s-helical IC2 and flexible IC3. Our results indicate that agonist binding induced different conformational rearrangements of these characteristic functional switches in adenosine-A2AAR and apo-A2AAR.
基金the National Distinguished PhD Dissertations(200521)the National Natural Science Foundation of China(Grant No.60736208)
文摘Taking the famous genetic toggle switch as an example,we numerically investigated the effect of noise on bistability.We found that extrinsic noise resulting from stochastic fluctuations in synthesis and degradation rates and from the environmental fluctuation in gene regulatory processes can induce coherent switch,and that there is an optimal noise intensity such that the noise not only can induce this switch,but also can amplify a weak input signal.In addition,we found that the intrinsic noise introduced through the Poisson τ-leap algorithm cannot induce such a switch.
