Improved conformational sampling techniques and their applications to biomolecular simulations.

摘要

Despite the increase in the number of studies using molecular dynamics to simulate the thermodynamic and dynamic properties of biomolecules, the effort in improvement of sampling efficiency in the system with rugged energy surface has never been stopped.; In this dissertation, we first describe a strategy, which successfully extends the locally enhanced sampling (LES) to work properly within the generalized Born (GB) implicit solvent model. Application of the resulting method to the study of a conformational change in an RNA UUCG tetraloop reveals that the combined GB+LES approach is more efficient than use of either GB or LES alone. In addition, it is demonstrated that the combined method significantly improves the ability of LES copies to explore independent transition paths as compared to LES simulations in explicit water.; The replica exchange method (REM) has been widely used in peptide and small protein folding studies. For large systems, however, applying REM can be costly since the number of replicas needed increases as the square root of the number of degrees of freedom in the system. Often, enhanced sampling is only needed for a subset of atoms, such as a loop region of a large protein or a small ligand binding to a receptor. For these cases, we derived two variant replica exchange methods, partial replica exchange method (PREM) and local replica exchange method (LREM). We tested these two methods on the RNA tetraloop system and found that both methods were able to refine the loop region with dramatic improvement over standard REM approach.; In the last chapter, we summarize the molecular dynamics studies of four different DNA 13-mer sequences with G:C, G:A, 8oxoG:C and 8oxoG:A base pairs. Our simulation results confirmed the predominance of the normal anti:anti form of the 8oxoG:C base pair and the Hoogsteen syn:anti form of the 8oxoG:A pair. In the case of 8oxoG:A pair, we observed flipping of the 8oxoG, resulting in an anti → syn transition. In order to gain further insight into the details of this structure transition and local structural fluctuations, we applied our modified REM to the lesion site of the above four DNA systems and obtained probability distributions for alternate base pair conformations for each sequence. The combination of free dynamics and the thermodynamic data from REM provides new insights into the dynamic behavior of this system and how this behavior is affected by the chemical modifications involved in the oxidative damage.