| 1. |
- Boomsma, Wouter, et al.
(author)
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PHAISTOS: A framework for Markov chain Monte Carlo simulation and inference of protein structure.
- 2013
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In: Journal of Computational Chemistry. - : Wiley. - 1096-987X .- 0192-8651. ; 34:19, s. 1697-1705
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Journal article (peer-reviewed)abstract
- We present a new software framework for Markov chain Monte Carlo sampling for simulation, prediction, and inference of protein structure. The software package contains implementations of recent advances in Monte Carlo methodology, such as efficient local updates and sampling from probabilistic models of local protein structure. These models form a probabilistic alternative to the widely used fragment and rotamer libraries. Combined with an easily extendible software architecture, this makes PHAISTOS well suited for Bayesian inference of protein structure from sequence and/or experimental data. Currently, two force-fields are available within the framework: PROFASI and OPLS-AA/L, the latter including the generalized Born surface area solvent model. A flexible command-line and configuration-file interface allows users quickly to set up simulations with the desired configuration. PHAISTOS is released under the GNU General Public License v3.0. Source code and documentation are freely available from http://phaistos.sourceforge.net. The software is implemented in C++ and has been tested on Linux and OSX platforms. © 2013 Wiley Periodicals, Inc.
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| 2. |
- Harder, Tim, et al.
(author)
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An Efficient Null Model for Conformational Fluctuations in Proteins
- 2012
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In: Structure. - : Elsevier BV. - 0969-2126. ; 20:6, s. 1028-1039
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Journal article (peer-reviewed)abstract
- Protein dynamics play a crucial role in function, catalytic activity, and pathogenesis. Consequently, there is great interest in computational methods that probe the conformational fluctuations of a protein. However, molecular dynamics simulations are computationally costly and therefore are often limited to comparatively short timescales. TYPHON is a probabilistic method to explore the conformational space of proteins under the guidance of a sophisticated probabilistic model of local structure and a given set of restraints that represent nonlocal interactions, such as hydrogen bonds or disulfide bridges. The choice of the restraints themselves is heuristic, but the resulting probabilistic model is well-defined and rigorous. Conceptually, TYPHON constitutes a null model of conformational fluctuations under a given set of restraints. We demonstrate that TYPHON can provide information on conformational fluctuations that is in correspondence with experimental measurements. TYPHON provides a flexible, yet computationally efficient, method to explore possible conformational fluctuations in proteins.
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| 3. |
- Bottaro, Sandro, et al.
(author)
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Subtle Monte Carlo Updates in Dense Molecular Systems
- 2012
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In: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 8:2, s. 695-702
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Journal article (peer-reviewed)abstract
- Although Markov chain Monte Carlo (MC) simulation is a potentially powerful approach for exploring conformational space, it has been unable to compete with molecular dynamics (MD) in the analysis of high density structural states, such as the native state of globular proteins. Here, we introduce a kinetic algorithm, CRISP, that greatly enhances the sampling efficiency in all-atom MC simulations of dense systems. The algorithm is based on an exact analytical solution to the classic chain-closure problem, making it possible to express the interdependencies among degrees of freedom in the molecule as correlations in a multivariate Gaussian distribution. We demonstrate that our method reproduces structural variation in proteins with greater efficiency than current state-of-the-art Monte Carlo methods and has real-time simulation performance on par with molecular dynamics simulations. The presented results suggest our method as a valuable tool in the study of molecules in atomic detail, offering a potential alternative to molecular dynamics for probing long time-scale conformational transitions.
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| 4. |
- Tian, Pengfei, et al.
(author)
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Robust Estimation of Diffusion-Optimized Ensembles for Enhanced Sampling
- 2014
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In: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:2, s. 543-553
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Journal article (peer-reviewed)abstract
- The multicanonical, or flat-histogram, method is a common technique to improve the sampling efficiency of molecular simulations. The idea is that free-energy barriers in a simulation can be removed by simulating from a distribution where all values of a reaction coordinate are equally likely, and subsequently reweight the obtained statistics to recover the Boltzmann distribution at the temperature of interest. While this method has been successful in practice, the choice of a flat distribution is not necessarily optimal. Recently, it was proposed that additional performance gains could be obtained by taking the position-dependent diffusion coefficient into account, thus placing greater emphasis on regions diffusing slowly. Although some promising examples of applications of this approach exist, the practical usefulness of the method has been hindered by the difficulty in obtaining sufficiently accurate estimates of the diffusion coefficient. Here, we present a simple, yet robust solution to this problem. Compared to current state-of-the-art procedures, the new estimation method requires an order of magnitude fewer data to obtain reliable estimates, thus broadening the potential scope in which this technique can be applied in practice.
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