Browsing by Author "Zang, Tianwu"

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    Advanced Computational Methods for High-accuracy Refinement of Protein Low-quality Models
    (2016-11-10) Zang, Tianwu; Ma, Jianpeng
    Predicting the 3-dimentional structure of protein has been a major interest in the modern computational biology. While lots of successful methods can generate models with 3~5Å root-mean-square deviation (RMSD) from the solution, the progress of refining these models is quite slow. It is therefore urgently needed to develop effective methods to bring low-quality models to higher-accuracy ranges (e.g., less than 2 Å RMSD). In this thesis, I present several novel computational methods to address the high-accuracy refinement problem. First, an enhanced sampling method, named parallel continuous simulated tempering (PCST), is developed to accelerate the molecular dynamics (MD) simulation. Second, two energy biasing methods, Structure-Based Model (SBM) and Ensemble-Based Model (EBM), are introduced to perform targeted sampling around important conformations. Third, a three-step method is developed to blindly select high-quality models along the MD simulation. These methods work together to make significant refinement of low-quality models without any knowledge of the solution. The effectiveness of these methods is examined in different applications. Using the PCST-SBM method, models with higher global distance test scores (GDT_TS) are generated and selected in the MD simulation of 18 targets from the refinement category of the 10th Critical Assessment of Structure Prediction (CASP10). In addition, in the refinement test of two CASP10 targets using the PCST-EBM method, it is indicated that EBM may bring the initial model to even higher-quality levels. Furthermore, a multi-round refinement protocol of PCST-SBM improves the model quality of a protein to the level that is sufficient high for the molecular replacement in X-ray crystallography. Our results justify the crucial position of enhanced sampling in the protein structure prediction and demonstrate that a considerable improvement of low-accuracy structures is still achievable with current force fields.
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    Enhanced Sampling Method in Statistical Physics and Large-Scale Molecular Simulation of Complex Systems
    (2014-04-25) Zang, Tianwu; Ma, Jianpeng; Kiang, Ching-Hwa; Raphael, Robert M.
    In large-scale complex systems, traditional computational methods in equilibrium statistical mechanics such as Monte Carlo simulation and molecular dynamics in canonical ensemble often face the broken ergodicity issue, which highly reduces the performance and accuracy of simulation. The past decades have witnessed the development of generalized ensemble, which has significantly enhanced the efficiency of molecular simulation. In this thesis, we get a review of typical generalized ensembles, such as multi-canonical ensemble, parallel tempering, simulating tempering and continuous simulated tempering (CST). We also present a method called parallel continuous simulated tempering(PCST) for enhanced sampling in studying large complex. It mainly inherits and CST method in previous work, while adopts the spirit of parallel tempering, by employing multiple copies with different temperature distributions. The sampling efficiency of PCST was tested in two-dimensional Ising model, Lennard-Jones liquid and all-atom folding simulation of a small globular protein trp-cage in explicit solvent. The results demonstrate that the PCST method has significantly improved sampling efficiency compared with other methods and it is particularly effective in simulating systems with long relaxation time or correlation time.
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    Parallel continuous simulated tempering and its applications in large-scale molecular simulations
    (AIP Publishing, 2014) Zang, Tianwu; Yu, Linglin; Zhang, Chong; Ma, Jianpeng; Bioengineering
    In this paper, we introduce a parallel continuous simulated tempering (PCST) method for enhanced sampling in studying large complex systems. It mainly inherits the continuous simulated tempering (CST) method in our previous studies [C. Zhang and J. Ma, J. Chem. Phys. 130, 194112 (2009); C. Zhang and J. Ma, J. Chem. Phys. 132, 244101 (2010)], while adopts the spirit of parallel tempering (PT), or replica exchange method, by employing multiple copies with different temperature distributions. Differing from conventional PT methods, despite the large stride of total temperature range, the PCST method requires very few copies of simulations, typically 2–3 copies, yet it is still capable of maintaining a high rate of exchange between neighboring copies. Furthermore, in PCST method, the size of the system does not dramatically affect the number of copy needed because the exchange rate is independent of total potential energy, thus providing an enormous advantage over conventional PT methods in studying very large systems. The sampling efficiency of PCST was tested in two-dimensional Ising model, Lennard-Jones liquid and all-atom folding simulation of a small globular protein trp-cage in explicit solvent. The results demonstrate that the PCST method significantly improves sampling efficiency compared with other methods and it is particularly effective in simulating systems with long relaxation time or correlation time. We expect the PCST method to be a good alternative to parallel tempering methods in simulating large systems such as phase transition and dynamics of macromolecules in explicit solvent.