PHAISTOS: A framework for Markov chain Monte Carlo simulation and inference of protein structure

Boomsma, Wouter; Frellsen, Jes; Harder, Tim; Bottaro, Sandro; Johansson, Kristoffer E.; Tian, Pengfei; Stovgaard, Kasper; Andreetta, Christian; Olsson, Simon; Valentin, Jan Brink; Antonov, Lubomir D.; Christensen, Anders S.; Borg, Mikael; Jensen, Jan H.; Lindorff‐Larsen, Kresten; Ferkinghoff‐Borg, Jesper; Hamelryck, Thomas

doi:10.1002/jcc.23292

Cited by 46 publications

(60 citation statements)

References 47 publications

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“…When using the latter, the CS-TORUS bias was included in the acceptance criterion of the biased Gaussian step, to ensure that both moves sample from the same distribution (SI Appendix). Simulations were conducted using the PHAISTOS software package (35), except for the unbiased simulation of Top7-Cfr, for which we used the PROFASI software package (34) (with identical settings). All simulations were conducted using generalized ensembles in the MUNINN software library (36).…”

Section: Methodsmentioning

confidence: 99%

Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts

Boomsma

Tian

Frellsen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Methods of protein structure determination based on NMR chemical shifts are becoming increasingly common. The most widely used approaches adopt the molecular fragment replacement strategy, in which structural fragments are repeatedly reassembled into different complete conformations in molecular simulations. Although these approaches are effective in generating individual structures consistent with the chemical shift data, they do not enable the sampling of the conformational space of proteins with correct statistical weights. Here, we present a method of molecular fragment replacement that makes it possible to perform equilibrium simulations of proteins, and hence to determine their free energy landscapes. This strategy is based on the encoding of the chemical shift information in a probabilistic model in Markov chain Monte Carlo simulations. First, we demonstrate that with this approach it is possible to fold proteins to their native states starting from extended structures. Second, we show that the method satisfies the detailed balance condition and hence it can be used to carry out an equilibrium sampling from the Boltzmann distribution corresponding to the force field used in the simulations. Third, by comparing the results of simulations carried out with and without chemical shift restraints we describe quantitatively the effects that these restraints have on the free energy landscapes of proteins. Taken together, these results demonstrate that the molecular fragment replacement strategy can be used in combination with chemical shift information to characterize not only the native structures of proteins but also their conformational fluctuations.

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Section: Methodsmentioning

confidence: 99%

Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts

Boomsma

Tian

Frellsen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The so-called “concerted rotations involving self-consistent proposals” (CRISP) move was combined with an implicit solvent description and was found to sample the conformational ensemble of ubiquitin and other proteins more efficiently than the CRA move set [92]. The CRISP move along with CRA, crankshaft, pivot, and other MC move sets has been implemented in a program suite called “Phaistos” for rapid conformational sampling of proteins in implicit solvents [93]. …”

Section: Introductionmentioning

confidence: 99%

Atomistic Monte Carlo Simulation of Lipid Membranes

Wüstner

Sklenar

2014

IJMS

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Biological membranes are complex assemblies of many different molecules of which analysis demands a variety of experimental and computational approaches. In this article, we explain challenges and advantages of atomistic Monte Carlo (MC) simulation of lipid membranes. We provide an introduction into the various move sets that are implemented in current MC methods for efficient conformational sampling of lipids and other molecules. In the second part, we demonstrate for a concrete example, how an atomistic local-move set can be implemented for MC simulations of phospholipid monomers and bilayer patches. We use our recently devised chain breakage/closure (CBC) local move set in the bond-/torsion angle space with the constant-bond-length approximation (CBLA) for the phospholipid dipalmitoylphosphatidylcholine (DPPC). We demonstrate rapid conformational equilibration for a single DPPC molecule, as assessed by calculation of molecular energies and entropies. We also show transition from a crystalline-like to a fluid DPPC bilayer by the CBC local-move MC method, as indicated by the electron density profile, head group orientation, area per lipid, and whole-lipid displacements. We discuss the potential of local-move MC methods in combination with molecular dynamics simulations, for example, for studying multi-component lipid membranes containing cholesterol.

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“…Using these methods, exploring a protein's conformational space consists of incrementally building a graph whose nodes are conformations and whose edges represent potential transitions between them (Al-Bluwi et al, 2012; Gipson et al, 2012). SIMS follows a “coarse-grained” approach, similarly to MD-like methods using coarse-grained force fields (Davtyan et al, 2012), Monte-Carlo-based simulations (Sim et al, 2012; Boomsma et al, 2013), methods using elastic network models (López-Blanco and Chacón, 2016), or other robotics-inspired conformational sampling methods (Devaurs et al, 2013, 2015). …”

Section: Methodsmentioning

confidence: 99%

Coarse-Grained Conformational Sampling of Protein Structure Improves the Fit to Experimental Hydrogen-Exchange Data

Devaurs

Antunes

Papanastasiou

et al. 2017

Front. Mol. Biosci.

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Monitoring hydrogen/deuterium exchange (HDX) undergone by a protein in solution produces experimental data that translates into valuable information about the protein's structure. Data produced by HDX experiments is often interpreted using a crystal structure of the protein, when available. However, it has been shown that the correspondence between experimental HDX data and crystal structures is often not satisfactory. This creates difficulties when trying to perform a structural analysis of the HDX data. In this paper, we evaluate several strategies to obtain a conformation providing a good fit to the experimental HDX data, which is a premise of an accurate structural analysis. We show that performing molecular dynamics simulations can be inadequate to obtain such conformations, and we propose a novel methodology involving a coarse-grained conformational sampling approach instead. By extensively exploring the intrinsic flexibility of a protein with this approach, we produce a conformational ensemble from which we extract a single conformation providing a good fit to the experimental HDX data. We successfully demonstrate the applicability of our method to four small and medium-sized proteins.

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PHAISTOS: A framework for Markov chain Monte Carlo simulation and inference of protein structure

Cited by 46 publications

References 47 publications

Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts

Equilibrium simulations of proteins using molecular fragment replacement and NMR chemical shifts

Atomistic Monte Carlo Simulation of Lipid Membranes

Coarse-Grained Conformational Sampling of Protein Structure Improves the Fit to Experimental Hydrogen-Exchange Data

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