Fitting side-chain NMR relaxation data using molecular simulations

AbstractProteins display a wealth of dynamical motions that can be probed using both experiments and simulations. We present an approach to integrate side chain NMR relaxation measurements with molecular dynamics simulations to study the structure and dynamics of these motions. The approach, which we term ABSURDer (Average Block Selection Using Relaxation Data with Entropy Restraints) can be used to find a set of trajectories that are in agreement with relaxation measurements. We apply the method to deuterium relaxation measurements in T4 lysozyme, and show how it can be used to integrate the accuracy of the NMR measurements with the molecular models of protein dynamics afforded by the simulations. We show how fitting of dynamic quantities leads to improved agreement with static properties, and highlight areas needed for further improvements of the approach.

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How much entropy is contained in NMR relaxation parameters?

10.33774/chemrxiv-2021-l686w ◽

2021 ◽

Cited By ~ 1

Author(s):

Falk Hoffmann ◽

Frans A. A. Mulder ◽

Lars V. Schäfer

Keyword(s):

Time Scales ◽

Nmr Relaxation ◽

Md Simulations ◽

Side Chain ◽

Thermodynamic Quantities ◽

T4 Lysozyme ◽

Time Dynamics ◽

Relaxation Parameters ◽

Relaxation Experiments ◽

Short Time

Solution-state NMR relaxation experiments are the cornerstone to study internalprotein dynamics at atomic resolution on time scales that are faster than the overallrotational tumbling time,τR. Since the motions described by NMR relaxation pa-rameters are connected to thermodynamic quantities like conformational entropies, thequestion arises how much of the total entropy is contained within this tumbling time.Using all-atom molecular dynamics (MD) simulations of T4 lysozyme, we found thatentropy build-up is rather fast for the backbone, such that the majority of the entropyis indeed contained in the short-time dynamics. In contrast, the contribution of slowdynamics of side chains on time scales beyondτRon the side chain conformationalentropy is significant and should be taken into account for the extraction of accuratethermodynamic properties.

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Methylguanidinium at the Air/Water Interface: A Simulation Study with the Drude Polarizable Force Field

10.26434/chemrxiv.12973178.v2 ◽

2020 ◽

Author(s):

Jian Zhu ◽

Jing Huang

Keyword(s):

Force Field ◽

Model Compound ◽

Side Chain ◽

Water Interface ◽

Polarizable Force Field ◽

Polarization Effects ◽

Structure And Dynamics ◽

Arginine Side Chain ◽

Air Water Interface ◽

Dynamics Simulations

<div>Methylguanidinium is an important molecular ion which also serves as the model compound for arginine side chain. We studied the structure and dynamics of methylguanidium ion at the air/water interface by molecular dynamics simulations employing the Drude polarizable force field. We found out that methylguanidinium accumulate on the interface with a majority adopting tilted conformations. We also demonstrated that methylguanidinium and guanidinium ions have different preference towards the air/water interface. Our results illustrate the importance to explicitly include the electronic polarization effects in modeling interfacial properties.</div><div><br> </div>

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Double mutant of chymotrypsin inhibitor 2 stabilized through increased conformational entropy

10.1101/2021.11.18.469114 ◽

2021 ◽

Author(s):

Yulian Gavrilov ◽

Felix Kümmerer ◽

Simone Orioli ◽

Andreas Prestel ◽

Kresten Lindorff-Larsen ◽

...

Keyword(s):

Double Mutant ◽

Conformational Dynamics ◽

Nmr Relaxation ◽

Conformational Heterogeneity ◽

Native State ◽

Chymotrypsin Inhibitor 2 ◽

Relaxation Measurements ◽

The Stability ◽

Dynamics Simulations ◽

Mutant Forms

The conformational heterogeneity of a folded protein can affect both its function but also stability and folding. We recently discovered and characterized a stabilized double mutant (L49I/I57V) of the protein CI2 and showed that state-of-the-art prediction methods could not predict the increased stability relative to the wild-type protein. Here we have examined whether changed native state dynamics, and resulting entropy changes, can explain the stability changes in the double mutant protein, as well as the two single mutant forms. We have combined NMR relaxation measurements of the ps-ns dynamics of amide groups in the backbone and the methyl groups in the side-chains with molecular dynamics simulations to quantify the native state dynamics. The NMR experiments reveal that the mutations have different effects on the conformational flexibility of CI2: A reduction in conformational dynamics (and entropy) of the native state of L49I variant correlates with its decreased stability, while increased dynamics of the I57V and L49I/I57V variants correlates with their increased stability. These findings suggest that explicitly accounting for changes in native state entropy might be needed to improve the predictions of the effect of mutations on protein stability.

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