<scp>MkVsites</scp>: A tool for creating <scp>GROMACS</scp> virtual sites parameters to increase performance in all‐atom molecular dynamics simulations

Larsson, Per; Kneiszl, Rosita; Marklund, Erik

doi:10.1002/jcc.26198

Cited by 19 publications

(17 citation statements)

References 17 publications

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“…The hormone was modelled using GAFF/BCC force field parameters 50 . Virtual sites 51 for the hormone were constructed using the MkVsites tool 52 , all bonds we constrained with LINCS 53 ), and SETTLE 54 to keep water molecules rigid, enabling a 4-fs time step in all subsequent simulations. Steepest descent energy minimization was carried out for both systems.…”

Section: Methodsmentioning

confidence: 99%

A hydrophobic ratchet entrenches molecular complexes

Hochberg

Liu

Marklund

et al. 2020

Nature

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103

108

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Most proteins assemble into multisubunit complexes 1 . The persistence of these complexes across evolutionary time is usually explained as the result of natural selection for functional properties that depend upon multimerization, like intersubunit allostery or the capacity to do mechanical work 2 . In many complexes, however, multimerization does not enable any known function 3 . An alternative explanation is that multimers could become entrenched if substitutions accumulate that are neutral in multimers but deleterious in monomers; purifying selection would then prevent reversion to the unassembled form, even if assembly per se does not enhance biological function 3 – 7 . Here we show that a hydrophobic mutational ratchet systematically entrenches molecular complexes. By applying ancestral protein reconstruction and biochemical assays to the evolution of steroid hormone receptors (SRs), we show that an ancient hydrophobic interface, conserved for hundreds of millions of years, is entrenched because exposing this interface to solvent reduces protein stability and causes aggregation, despite making no detectable contribution to function. Using structural bioinformatics, we show that a universal mutational propensity drives sites that are buried in multimeric interfaces to accumulate hydrophobic substitutions to levels not tolerated in monomers. In a database of hundreds of families of multimers, the majority show signatures of long-term hydrophobic entrenchment. It is therefore likely that many protein complexes persist because a simple ratchet-like mechanism entrenches them across evolutionary time, even when they are functionally gratuitous.

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Section: Methodsmentioning

confidence: 99%

A hydrophobic ratchet entrenches molecular complexes

Hochberg

Liu

Marklund

et al. 2020

Nature

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103

108

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“…The amber99sb force field was utilized for all simulations [ 62 ], modified to include parameters for iD and F [ 63 ]. The MkVsites tool provided virtual sites and dummy-mass constructions for F [ 64 ]. Structures were placed in a dodecahedral box under periodic boundary conditions, solvated using the TIP3P water model [ 65 ] and neutralized in a 154 mM saline solution by adding NaCl.…”

Section: Methodsmentioning

confidence: 99%

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status

et al. 2021

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Noroviruses are the major cause of viral gastroenteritis and re-emerge worldwide every year, with GII.4 currently being the most frequent human genotype. The norovirus capsid protein VP1 is essential for host immune response. The P domain mediates cell attachment via histo blood-group antigens (HBGAs) in a strain-dependent manner but how these glycan-interactions actually relate to cell entry remains unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) is used to investigate glycan-induced protein dynamics in P dimers of different strains, which exhibit high structural similarity but different prevalence in humans. While the almost identical strains GII.4 Saga and GII.4 MI001 share glycan-induced dynamics, the dynamics differ in the emerging GII.17 Kawasaki 308 and rare GII.10 Vietnam 026 strain. The structural aspects of glycan binding to fully deamidated GII.4 P dimers have been investigated before. However, considering the high specificity and half-life of N373D under physiological conditions, large fractions of partially deamidated virions with potentially altered dynamics in their P domains are likely to occur. Therefore, we also examined glycan binding to partially deamidated GII.4 Saga and GII.4 MI001 P dimers. Such mixed species exhibit increased exposure to solvent in the P dimer upon glycan binding as opposed to pure wildtype. Furthermore, deamidated P dimers display increased flexibility and a monomeric subpopulation. Our results indicate that glycan binding induces strain-dependent structural dynamics, which are further altered by N373 deamidation, and hence hint at a complex role of deamidation in modulating glycan-mediated cell attachment in GII.4 strains.

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“…The amber99sb force field was utilized for all simulations [38], modified to include parameters for iD and F [39]. The MkVsites tool provided virtual sites and dummy-mass constructions for F [40]. Structures were placed in a dodecahedral box under periodic boundary conditions, solvated using the TIP3P water model [41], and neutralized in a 154 mM saline solution by adding NaCl.…”

Section: Simulationsmentioning

confidence: 99%

Glycan-induced protein dynamics in human norovirus P dimers depend on virus strain and deamidation status

Duelfer

Yan

Brodmerkel

et al. 2020

Preprint

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Noroviruses are the major cause of gastroenteritis and re-emerge worldwide every year, with GII.4 currently being the most frequent human genotype. The norovirus capsid protein VP1 is essential for host immune response. The P domain mediates cell attachment via histo blood-group antigens (HBGAs) in a strain-dependent manner but how these glycan-interactions actually relate to cell entry remains unclear. Here, hydrogen/deuterium exchange mass spectrometry (HDX-MS) is used to investigate glycan-induced protein dynamics in P dimers of different strains, which exhibit high structural similarity but different prevalence in humans. While the almost identical strains GII.4 Saga and GII.4 MI001 share glycan-induced dynamics, the dynamics differ in the emerging GII.17 Kawasaki 308 and rare GII.10 Vietnam 026 strain. We also further examine structural effects of N373 deamidation upon glycan binding in partially deamidated GII.4 P dimers, which are likely present during infection. Such mixed species exhibit increased exposure to solvent in the P dimer upon glycan binding as opposed to pure wildtype. Furthermore, deamidated P dimers display increased flexibility and a monomeric population. Our results indicate that glycan binding induces strain-dependent structural dynamics, which are further altered by N373 deamidation, and hence hint at a role of deamidation in modulating cell attachment and entry in GII.4 strains.

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MkVsites: A tool for creating GROMACS virtual sites parameters to increase performance in all‐atom molecular dynamics simulations

Cited by 19 publications

References 17 publications

A hydrophobic ratchet entrenches molecular complexes

A hydrophobic ratchet entrenches molecular complexes

Glycan-Induced Protein Dynamics in Human Norovirus P Dimers Depend on Virus Strain and Deamidation Status

Glycan-induced protein dynamics in human norovirus P dimers depend on virus strain and deamidation status

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