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A Riemann metric approach to optimal sampling of multidimensional free energy landscapes
KTH, School of Engineering Sciences (SCI), Physics.
KTH, School of Engineering Sciences (SCI), Physics.
KTH, School of Engineering Sciences (SCI), Physics.
(English)In: Physical Review X, ISSN 2160-3308, E-ISSN 2160-3308Article in journal (Refereed) Submitted
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.

Place, publisher, year, edition, pages
Stockholm.
Keyword [en]
Molecular dynamics, enhanced sampling, diffusion
National Category
Biophysics
Research subject
Biological Physics
Identifiers
URN: urn:nbn:se:kth:diva-217876OAI: oai:DiVA.org:kth-217876DiVA: diva2:1158176
Note

QC 20171211

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Optimizing sampling of important events in complex biomolecular systems
Open this publication in new window or tab >>Optimizing sampling of important events in complex biomolecular systems
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. 47 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2017:72
Keyword
molecular dynamics, free energy calculation, adaptive sampling, extended ensembles, membrane proteins, DNA
National Category
Biophysics
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-217837 (URN)978-91-7729-599-0 (ISBN)
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

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