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Conformational Disorder and Dynamics of Proteins Sensed by Raman Optical Activity.

ABSTRACT: Raman optical activity (ROA) spectra of proteins hold a lot of information about their structure in solution. To create a better understanding of the ROA spectra of, among others, the intrinsically disordered proteins (IDPs), involved in neurodegenerative diseases, the effect of conformational disorder and dynamics on the ROA spectra was studied. Density functional theory (DFT) calculations of small ensembles of model peptides with increasing disorder show that the ROA patterns of ?-helical and polyproline II (PPII) structure reflect the average backbone angles in the ensemble. The amide III region in the ROA spectra of the ?-helical peptides is shown to retain its typical -/+/+ pattern, while the amide III region of PPII secondary structure diminishes in intensity with increasing structural disorder. The results show that the ROA spectra of IDPs hence more likely stem from short stretches of well-defined PPII helices rather than a very flexible chain. Further DFT calculations support that mixing of PPII with helical secondary structure is consistent with experimental spectra of IDPs, while mixing with ?-strand results in spectral patterns that are not observed experimentally. The detailed information obtained from these results contributes to a better understanding of the spectrum-structure relation.

SUBMITTER: Mensch C

PROVIDER: S-EPMC6644472 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Conformational Disorder and Dynamics of Proteins Sensed by Raman Optical Activity.

Mensch Carl C Bultinck Patrick P Johannessen Christian C

ACS omega 20181010 10

Raman optical activity (ROA) spectra of proteins hold a lot of information about their structure in solution. To create a better understanding of the ROA spectra of, among others, the intrinsically disordered proteins (IDPs), involved in neurodegenerative diseases, the effect of conformational disorder and dynamics on the ROA spectra was studied. Density functional theory (DFT) calculations of small ensembles of model peptides with increasing disorder show that the ROA patterns of α-helical and ...[more]

PMID: 31458018

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Project description:All-atom molecular dynamics simulations are widely used to study the flexibility of protein conformations. However, enhanced sampling techniques are required for simulating protein dynamics that occur on the millisecond timescale. In this work, we show that torsional molecular dynamics simulations enhance protein conformational sampling by performing conformational search in the low-frequency torsional degrees of freedom. In this article, we use our recently developed torsional-dynamics method called Generalized Newton-Euler Inverse Mass Operator (GNEIMO) to study the conformational dynamics of four proteins. We investigate the use of the GNEIMO method in simulations of the conformationally flexible proteins fasciculin and calmodulin, as well as the less flexible crambin and bovine pancreatic trypsin inhibitor. For the latter two proteins, the GNEIMO simulations with an implicit-solvent model reproduced the average protein structural fluctuations and sample conformations similar to those from Cartesian simulations with explicit solvent. The application of GNEIMO with replica exchange to the study of fasciculin conformational dynamics produced sampling of two of this protein's experimentally established conformational substates. Conformational transition of calmodulin from the Ca(2+)-bound to the Ca(2+)-free conformation occurred readily with GNEIMO simulations. Moreover, the GNEIMO method generated an ensemble of conformations that satisfy about half of both short- and long-range interresidue distances obtained from NMR structures of holo to apo transitions in calmodulin. Although unconstrained all-atom Cartesian simulations have failed to sample transitions between the substates of fasciculin and calmodulin, GNEIMO simulations show the transitions in both systems. The relatively short simulation times required to capture these long-timescale conformational dynamics indicate that GNEIMO is a promising molecular-dynamics technique for studying domain motion in proteins.

Dataset Information

Conformational Disorder and Dynamics of Proteins Sensed by Raman Optical Activity.

Publications

Conformational Disorder and Dynamics of Proteins Sensed by Raman Optical Activity.

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