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Mapping conformational ensembles of a? oligomers in molecular dynamics simulations.

ABSTRACT: Although the oligomers formed by A? peptides appear to be the primary cytotoxic species in Alzheimer's disease, detailed information about their structures appears to be lacking. In this article, we use exhaustive replica exchange molecular dynamics and an implicit solvent united-atom model to study the structural properties of A? monomers, dimers, and tetramers. Our analysis suggests that the conformational ensembles of A? dimers and tetramers are very similar, but sharply distinct from those sampled by the monomers. The key conformational difference between monomers and oligomers is the formation of ?-structure in the oligomers occurring together with the loss of intrapeptide interactions and helix structure. Our simulations indicate that, independent of oligomer order, the A? aggregation interface is largely confined to the sequence region 10-23, which forms the bulk of interpeptide interactions. We show that the fractions of ? structure computed in our simulations and measured experimentally are in good agreement.

SUBMITTER: Kim S

PROVIDER: S-EPMC2941018 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Mapping conformational ensembles of aβ oligomers in molecular dynamics simulations.

Kim Seongwon S Takeda Takako T Klimov Dmitri K DK

Biophysical journal 20100901 6

Although the oligomers formed by Aβ peptides appear to be the primary cytotoxic species in Alzheimer's disease, detailed information about their structures appears to be lacking. In this article, we use exhaustive replica exchange molecular dynamics and an implicit solvent united-atom model to study the structural properties of Aβ monomers, dimers, and tetramers. Our analysis suggests that the conformational ensembles of Aβ dimers and tetramers are very similar, but sharply distinct from those s ...[more]

PMID: 20858441

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Project description:Far from the static, idealized conformations deposited into structural databases, proteins are highly dynamic molecules that undergo conformational changes on temporal and spatial scales that may span several orders of magnitude. These conformational changes, often intimately connected to the functional roles that proteins play, may be obscured by traditional biophysical techniques. Over the past 40 years, molecular dynamics (MD) simulations have complemented these techniques by providing the "hidden" atomistic details that underlie protein dynamics. However, there are limitations of the degree to which molecular simulations accurately and quantitatively describe protein motions. Here we show that although four molecular dynamics simulation packages (AMBER, GROMACS, NAMD, and ilmm) reproduced a variety of experimental observables for two different proteins (engrailed homeodomain and RNase H) equally well overall at room temperature, there were subtle differences in the underlying conformational distributions and the extent of conformational sampling obtained. This leads to ambiguity about which results are correct, as experiment cannot always provide the necessary detailed information to distinguish between the underlying conformational ensembles. However, the results with different packages diverged more when considering larger amplitude motion, for example, the thermal unfolding process and conformational states sampled, with some packages failing to allow the protein to unfold at high temperature or providing results at odds with experiment. While most differences between MD simulations performed with different packages are attributed to the force fields themselves, there are many other factors that influence the outcome, including the water model, algorithms that constrain motion, how atomic interactions are handled, and the simulation ensemble employed. Here four different MD packages were tested each using best practices as established by the developers, utilizing three different protein force fields and three different water models. Differences between the simulated protein behavior using two different packages but the same force field, as well as two different packages with different force fields but the same water models and approaches to restraining motion, show how other factors can influence the behavior, and it is incorrect to place all the blame for deviations and errors on force fields or to expect improvements in force fields alone to solve such problems.

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

Mapping conformational ensembles of a? oligomers in molecular dynamics simulations.

Publications

Mapping conformational ensembles of aβ oligomers in molecular dynamics simulations.

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