Transient Access to the Protein Interior: Simulation versus NMR

Persson, Filip; Halle, Bertil

doi:10.1021/ja403405d

Cited by 57 publications

(89 citation statements)

References 70 publications

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“…In this work, we used this lower bound on the exchange time to fully map the solvent accessibility of the proteins' interior. As already probed for other globular proteins 49,77,78 , for these two G-domains, the probability that a water molecule persists in the hydration shell as a function of time, N w (t), extends with a long tail in the nanoseconds range, as shown in the insets of 1. When performing an exponential fit of this long tail (t> 5 ns) we recover average characteristic times of ⟨τ slow ⟩ 41 ns and 16 ns for and , respectively.…”

Section: The Exchange Kinetics Of Internal Water Moleculesmentioning

confidence: 62%

“…The number of internal waters fluctuates over time and the penetration/escape dynamics correlates with the breathing soft-modes of the protein that visits different conformational states 78,87 . For our proteins, the fluctuations are rather high (~ 40%) and have characteristic oscillation period ranging from tenths to one hundred nanoseconds.…”

Section: Hydration and Global Protein Flexibilitymentioning

confidence: 99%

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Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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In this work we address the question whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologues G-domains of different stability: the mesophilic G domain of the Elongation-Factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time-scale we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favourable for both systems, with the hyperthermophilic protein offering a slightly more favourable environment to host water molecules. We estimate that under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that at extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G-domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

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Section: The Exchange Kinetics Of Internal Water Moleculesmentioning

confidence: 62%

Section: Hydration and Global Protein Flexibilitymentioning

confidence: 99%

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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“…34 Such studies provide unique insights into intermittent structural dynamics and transient solvent penetration of globular proteins. 28,34 Corresponding water 1 H MRD studies are less useful for extracting clear-cut biophysical information, since the smaller coupling constant (ω D is an order of magnitude smaller than ω Q ) allows more labile protons to contribute to R 1 in addition to well-defined internal hydration sites. Nevertheless, 1 H MRD can sometimes be a useful complement to water 2 H MRD measurements 20 and, in addition, can be used to study cosolvent interactions with proteins or other macromolecules.…”

Section: Discussionmentioning

confidence: 99%

“…6 In both cases, exchange randomizes the orientation of the interaction tensor effectively instantaneously because, in the B state, the molecule rotates on a time scale that is short compared to the mean survival time τ A in an A site. 6,28 The spin dynamics can then be described by a stochastic Liouville equation involving an exchange operator W with the nonzero matrix elements in the site basis given by 6…”

Section: Exchange Scenariosmentioning

confidence: 99%

Nuclear magnetic relaxation induced by exchange-mediated orientational randomization: Longitudinal relaxation dispersion for a dipole-coupled spin-1/2 pair

Chang

Halle

2013

The Journal of Chemical Physics

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In complex biological or colloidal samples, magnetic relaxation dispersion (MRD) experiments using the field-cycling technique can characterize molecular motions on time scales ranging from nanoseconds to microseconds, provided that a rigorous theory of nuclear spin relaxation is available. In gels, cross-linked proteins, and biological tissues, where an immobilized macromolecular component coexists with a mobile solvent phase, nuclear spins residing in solvent (or cosolvent) species relax predominantly via exchange-mediated orientational randomization (EMOR) of anisotropic nuclear (electric quadrupole or magnetic dipole) couplings. The physical or chemical exchange processes that dominate the MRD typically occur on a time scale of microseconds or longer, where the conventional perturbation theory of spin relaxation breaks down. There is thus a need for a more general relaxation theory. Such a theory, based on the stochastic Liouville equation (SLE) for the EMOR mechanism, is available for a single quadrupolar spin I = 1. Here, we present the corresponding theory for a dipole-coupled spin-1/2 pair. To our knowledge, this is the first treatment of dipolar MRD outside the motional-narrowing regime. Based on an analytical solution of the spatial part of the SLE, we show how the integral longitudinal relaxation rate can be computed efficiently. Both like and unlike spins, with selective or non-selective excitation, are treated. For the experimentally important dilute regime, where only a small fraction of the spin pairs are immobilized, we obtain simple analytical expressions for the auto-relaxation and cross-relaxation rates which generalize the well-known Solomon equations. These generalized results will be useful in biophysical studies, e.g

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“…This is the case, for example, for chemical exchange of labile macromolecular protons with bulk water and for physical exchange of trapped (internal) water molecules with bulk water. 20,23 We can then ignore all dipole couplings among the labile spins in state B. If so desired, the small and frequencyindependent relaxation contribution from fast modulation of dipole couplings in state B can be added to the final expression for the overall relaxation rate.…”

Section: General Casementioning

confidence: 99%

Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems

Chang

Halle

2016

The Journal of Chemical Physics

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On the theory of the proton dipolar-correlation effect as a method for investigation of segmental displacement in polymer melts The Journal of Chemical Physics 147, 074904 (2017); 10.1063/1.4998184 THE JOURNAL OF CHEMICAL PHYSICS 144, 084202 (2016) Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems In aqueous systems with immobilized macromolecules, including biological tissue, the longitudinal spin relaxation of water protons is primarily induced by exchange-mediated orientational randomization (EMOR) of intra-and intermolecular magnetic dipole-dipole couplings. We have embarked on a systematic program to develop, from the stochastic Liouville equation, a general and rigorous theory that can describe relaxation by the dipolar EMOR mechanism over the full range of exchange rates, dipole coupling strengths, and Larmor frequencies. Here, we present a general theoretical framework applicable to spin systems of arbitrary size with symmetric or asymmetric exchange. So far, the dipolar EMOR theory is only available for a two-spin system with symmetric exchange. Asymmetric exchange, when the spin system is fragmented by the exchange, introduces new and unexpected phenomena. Notably, the anisotropic dipole couplings of non-exchanging spins break the axial symmetry in spin Liouville space, thereby opening up new relaxation channels in the locally anisotropic sites, including longitudinal-transverse cross relaxation. Such cross-mode relaxation operates only at low fields; at higher fields it becomes nonsecular, leading to an unusual inverted relaxation dispersion that splits the extreme-narrowing regime into two sub-regimes. The general dipolar EMOR theory is illustrated here by a detailed analysis of the asymmetric two-spin case, for which we present relaxation dispersion profiles over a wide range of conditions as well as analytical results for integral relaxation rates and time-dependent spin modes in the zero-field and motional-narrowing regimes. The general theoretical framework presented here will enable a quantitative analysis of frequency-dependent water-proton longitudinal relaxation in model systems with immobilized macromolecules and, ultimately, will provide a rigorous link between relaxation-based magnetic resonance image contrast and molecular parameters. C 2016 Author(s). All article content, except where otherwise noted, is licensed under a Creative Commons Attribution (CC BY) license

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Transient Access to the Protein Interior: Simulation versus NMR

Cited by 57 publications

References 70 publications

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

Nuclear magnetic relaxation induced by exchange-mediated orientational randomization: Longitudinal relaxation dispersion for a dipole-coupled spin-1/2 pair

Nuclear magnetic relaxation by the dipolar EMOR mechanism: General theory with applications to two-spin systems

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