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Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
KTH, School of Engineering Sciences (SCI), Physics.ORCID iD: 0000-0002-2679-3235
Department of Biomedical Sciences, University of Copenhagen, Denmark.
KTH, School of Engineering Sciences (SCI), Physics.
KTH, School of Engineering Sciences (SCI), Physics.
(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 [en]
aquaporin, molecular dynamics
National Category
Biophysics
Research subject
Biological Physics
Identifiers
URN: urn:nbn:se:kth:diva-217872OAI: oai:DiVA.org:kth-217872DiVA, id: diva2:1158147
Note

QC 20171206

Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-12-06Bibliographically 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. p. 47
Series
TRITA-FYS, ISSN 0280-316X ; 2017:72
Keywords
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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