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Optimizing sampling of important events in complex biomolecular systems
KTH, School of Engineering Sciences (SCI), Physics.ORCID iD: 0000-0002-2679-3235
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins and DNA are large, complex molecules that carry out biological functions essential to all life. Their successful operation relies on adopting specific structures, stabilized by intra-molecular interactions between atoms. The spatial and temporal resolution required to study the mechanics of these molecules in full detail can only be obtained using computer simulations of molecular models. In a molecular dynamics simulation, a trajectory of the system is generated, which allows mapping out the states and dynamics of the molecule. However, the time and length scales characteristic of biological events are many orders of magnitude larger than the resolution needed to accurately describe the microscopic processes of the atoms. To overcome this problem, sampling methods have been developed that enhance the occurrence of rare but important events, which improves the statistics of simulation data.

This thesis summarizes my work on developing the AWH method, an algorithm that adaptively optimizes sampling toward a target function and simultaneously finds and assigns probabilities to states of the simulated system. I have adapted AWH for use in molecular dynamics simulations. In doing so, I investigated the convergence of the method as a function of its input parameters and improved the robustness of the method. I have also worked on a generally applicable approach for calculating the target function in an automatic and non-arbitrary way. Traditionally, the target is set in an ad hoc way, while now sampling can be improved by 50% or more without extra effort. I have also used AWH to improve sampling in two biologically relevant applications. In one paper, we study the opening of a DNA base pair, which due to the stability of the DNA double helix only very rarely occurs spontaneously. We show that the probability of opening depends on both nearest-neighbor and longer-range sequence effect and furthermore structurally characterize the open states. In the second application the permeability and ammonia selectivity of the membrane protein aquaporin is investigated and we show that these functions are sensitive to specific mutations.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. , p. 47
Series
TRITA-FYS, ISSN 0280-316X ; 2017:72
Keywords [en]
molecular dynamics, free energy calculation, adaptive sampling, extended ensembles, membrane proteins, DNA
National Category
Biophysics
Research subject
Biological Physics
Identifiers
URN: urn:nbn:se:kth:diva-217837ISBN: 978-91-7729-599-0 (print)OAI: oai:DiVA.org:kth-217837DiVA, id: diva2:1158050
Public defence
2017-12-07, F3, Lindstedtsvägen 26, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20171117

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-11-21Bibliographically approved
List of papers
1. Accelerated weight histogram method for exploring free energy landscapes
Open this publication in new window or tab >>Accelerated weight histogram method for exploring free energy landscapes
2014 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 141, no 4, p. 044110-Article in journal (Refereed) Published
Abstract [en]

Calculating free energies is an important and notoriously difficult task for molecular simulations. The rapid increase in computational power has made it possible to probe increasingly complex systems, yet extracting accurate free energies from these simulations remains a major challenge. Fully exploring the free energy landscape of, say, a biological macromolecule typically requires sampling large conformational changes and slow transitions. Often, the only feasible way to study such a system is to simulate it using an enhanced sampling method. The accelerated weight histogram (AWH) method is a new, efficient extended ensemble sampling technique which adaptively biases the simulation to promote exploration of the free energy landscape. The AWH method uses a probability weight histogram which allows for efficient free energy updates and results in an easy discretization procedure. A major advantage of the method is its general formulation, making it a powerful platform for developing further extensions and analyzing its relation to already existing methods. Here, we demonstrate its efficiency and general applicability by calculating the potential of mean force along a reaction coordinate for both a single dimension and multiple dimensions. We make use of a non-uniform, free energy dependent target distribution in reaction coordinate space so that computational efforts are not wasted on physically irrelevant regions. We present numerical results for molecular dynamics simulations of lithium acetate in solution and chignolin, a 10-residue long peptide that folds into a beta-hairpin. We further present practical guidelines for setting up and running an AWH simulation.

Keywords
Ensemble Monte-Carlo, Molecular-Dynamics, Multicanonical Ensemble, Force-Field, Protein, Simulation, Systems, Distributions, Transitions, Chignolin
National Category
Biophysics
Identifiers
urn:nbn:se:kth:diva-151349 (URN)10.1063/1.4890371 (DOI)000340712200018 ()2-s2.0-84905648018 (Scopus ID)
Funder
EU, European Research Council, 258980
Note

QC 20140919

Available from: 2014-09-19 Created: 2014-09-18 Last updated: 2017-12-05Bibliographically approved
2. Sequence dependency of canonical base pair opening in the DNA double helix
Open this publication in new window or tab >>Sequence dependency of canonical base pair opening in the DNA double helix
2017 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 13, no 4, article id e1005463Article in journal (Refereed) Published
Abstract [en]

The flipping-out of a DNA base from the double helical structure is a key step of many cellular processes, such as DNA replication, modification and repair. Base pair opening is the first step of base flipping and the exact mechanism is still not well understood. We investigate sequence effects on base pair opening using extensive classical molecular dynamics simulations targeting the opening of 11 different canonical base pairs in two DNA sequences. Two popular biomolecular force fields are applied. To enhance sampling and calculate free energies, we bias the simulation along a simple distance coordinate using a newly developed adaptive sampling algorithm. The simulation is guided back and forth along the coordinate, allowing for multiple opening pathways. We compare the calculated free energies with those from an NMR study and check assumptions of the model used for interpreting the NMR data. Our results further show that the neighboring sequence is an important factor for the opening free energy, but also indicates that other sequence effects may play a role. All base pairs are observed to have a propensity for opening toward the major groove. The preferred opening base is cytosine for GC base pairs, while for AT there is sequence dependent competition between the two bases. For AT opening, we identify two non-canonical base pair interactions contributing to a local minimum in the free energy profile. For both AT and CG we observe long-lived interactions with water and with sodium ions at specific sites on the open base pair.

Place, publisher, year, edition, pages
Public Library of Science, 2017
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-209322 (URN)10.1371/journal.pcbi.1005463 (DOI)000402542900019 ()2-s2.0-85018285834 (Scopus ID)
Funder
EU, European Research Council, 258980Swedish Research Council, 2015-04992Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170619

Available from: 2017-06-19 Created: 2017-06-19 Last updated: 2017-11-17Bibliographically approved
3. Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
Open this publication in new window or tab >>Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
(English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322Article in journal (Refereed) Submitted
Abstract [en]

Aquaporin TIP2;1 is a protein channel that is permeable to both water and ammonia. Thestructural origin of ammonia selectivity remains obscure, but experiments have revealed that adouble mutation renders it impermeable to ammonia without affecting water permeability. Here,we aim to reproduce and explain these observations by performing an extensive mutationalstudy using microsecond long molecular dynamics simulations, applying two popular force fields.We calculate permeabilities and free energy profiles along the channel axis, for ammonia andwater. For one force field, the permeability of the double mutant decreases by a factor of 2.5 forwater and a factor of 4 for ammonia, thus increasing the selectivity for water. We attribute thiseffect to decreased entropy of water in the pore, due to the observed increase in pore–waterinteractions and narrower pore. Additionally, we observe spontaneous opening and closing ofthe pore on the cytosolic side, which suggests a gating mechanism for the pore. Our resultsshow that sampling methods and simulation times are sufficient to delineate even subtle effectsof mutations on structure and function and to capture important long-timescale events, butalso underline the importance of improving models further.

Keywords
aquaporin, molecular dynamics
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-217872 (URN)
Note

QC 20171206

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-12-06Bibliographically approved
4. A Riemann metric approach to optimal sampling of multidimensional free energy landscapes
Open this publication in new window or tab >>A Riemann metric approach to optimal sampling of multidimensional free energy landscapes
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Conformational transitions are central to many studies of high-dimensional model systems inbiophysics. For a Boltzmann distributions, crossing rates decrease exponentially with free energybarrier heights. Thus, in simulations exponential acceleration can be achieved by applying a biastuned such that a flat distribution is obtained along one or more well-chosen reaction coordinates.But flat is a subjective measure, unless a proper metric is used. Here we propose a multidimensionalmetric that defines uniform sampling such that it is invariant under nonlinear coordinate transfor-mations and which properly takes the local friction into account. We use the metric in combinationwith the accelerated weight histogram method, a free energy calculation and sampling method, toadaptively optimize sampling toward the target distribution prescribed by the metric. We demon-strate that for complex biomolecular sampling problems, such a DNA base-pair opening, samplingaccording to the metric can shorten the sampling time by a factor of 1.5. The metric is easy tocalculate and does not pose significant computational overhead.

Keywords
Molecular dynamics, enhanced sampling, diffusion
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-217876 (URN)
Note

QC 20171211

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2018-02-15Bibliographically approved

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