Different quantum mechanic methods have been evaluated for the calculation of binding modes and interactions between intercalators with different DNA base pairs by comparing with the results of MP2, which is very expensive, indicating that WB97XD method under 6-311+G* basis set is able to efficiently reproduce MP2 results. We discovered that the methylene blue trihydrate intercalated into the DNA base pairs, and DNA intercalation increased the distance between DNA base pairs, depending on the types of DNA bases. According to the binding energy results, it was found that the intercalation of methylene blue trihydrate into AA-TT base pair was more favorable in the orientation of nitrogen than other directions and intercalation, and the electric charge was transferred from methylene blue trihydrate to the AA-TT base pair. The analysis of change in the charge density shows that changes often take place in the heavy atom in the middle of the system which the charge density changes most remarkable.
The most important requirement of biomolecular modeling is to deal with electrostatic energies. The electrostatic polarizability is an important part of electrostatic interaction for simulation systems. However, AMBER, CHARMM, OPLS, GROMOS, MMFF force fields etc. used in the past mostly apply fixed atomic center point charge to describe electrostatic energies, and are not sufficient for considering the influence of the electrostatic polarization. The emergence of polarizable force fields has solved this problem. In recent years, quickly developed polarizable force fields have involved a lot of fields. The chapter relating to polarizable force fields spread over several aspects. Firstly, we reviewed the history of the classical force fields and compared with polarizable force fields to elucidate the advancements of polarizable force fields. Secondly, it is introduced that the application of polarizable force fields to small molecules and biological macromolecules simulation, including molecular design. Finally, a brief development trend and perspective is given on rapidly growing polarizable force fields.
The G-quadruplex DNA formed by the stack of guanines in human telomere sequence is a promising anticancer target. In this study we used the energy landscape theory to elucidate the folding mechanisms for the thrombin aptamer, Form 1 and Form 3 G-quadruplexes. The three G-quadruplexes were simulated with all-atom Gō-model. Results show that, the three G-quadruplexes fold through a two-state mechanism. In the initial stage of the folding process, the compact structures are formed. The G-quadruplexes need to form G-triplex structures on the basis of the compact structures before folding to the native states. The folding free energy barrier of Form 3 G-quadruplex is higher than thrombin aptamer and Form 1, which shows that the structure of Form 3 G-quadruplex has more stability than the other two G-quadruplexes.
Most proteins need to avoid the complex topologies when folding into the native structures, but some proteins with nontrivial topologies have been found in nature. Here we used protein unfolding simulations under high temperature and all-atom Gō-model to investigate the folding mechanisms for two trefoil knot proteins. Results show that, the contacts in β-sheet are important to the formation of knot protein, and if these contacts disappeared, the knot protein would be easy to untie. In the Gō-model simulations, the folding processes of the two knot proteins are similar. The compact structures of the two knot proteins with the native contacts in β-sheet are formed in transition state, and the intermediate state has loose C-terminal. This model also reveals the detailed folding mechanisms for the two proteins.
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