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Molecular dynamics simulations using temperature-enhanced essential dynamics replica exchange.

ABSTRACT: Today's standard molecular dynamics simulations of moderately sized biomolecular systems at full atomic resolution are typically limited to the nanosecond timescale and therefore suffer from limited conformational sampling. Efficient ensemble-preserving algorithms like replica exchange (REX) may alleviate this problem somewhat but are still computationally prohibitive due to the large number of degrees of freedom involved. Aiming at increased sampling efficiency, we present a novel simulation method combining the ideas of essential dynamics and REX. Unlike standard REX, in each replica only a selection of essential collective modes of a subsystem of interest (essential subspace) is coupled to a higher temperature, with the remainder of the system staying at a reference temperature, T(0). This selective excitation along with the replica framework permits efficient approximate ensemble-preserving conformational sampling and allows much larger temperature differences between replicas, thereby considerably enhancing sampling efficiency. Ensemble properties and sampling performance of the method are discussed using dialanine and guanylin test systems, with multi-microsecond molecular dynamics simulations of these test systems serving as references.

SUBMITTER: Kubitzki MB

PROVIDER: S-EPMC1877756 | biostudies-literature | 2007 Jun

REPOSITORIES: biostudies-literature

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Molecular dynamics simulations using temperature-enhanced essential dynamics replica exchange.

Kubitzki Marcus B MB de Groot Bert L BL

Biophysical journal 20070323 12

Today's standard molecular dynamics simulations of moderately sized biomolecular systems at full atomic resolution are typically limited to the nanosecond timescale and therefore suffer from limited conformational sampling. Efficient ensemble-preserving algorithms like replica exchange (REX) may alleviate this problem somewhat but are still computationally prohibitive due to the large number of degrees of freedom involved. Aiming at increased sampling efficiency, we present a novel simulation me ...[more]

PMID: 17384062

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Project description:The small heat shock proteins (sHSPs) are a virtually ubiquitous and diverse group of molecular chaperones that can bind and protect unfolding proteins from irreversible aggregation. It has been suggested that intrinsic disorder of the N-terminal arm (NTA) of sHSPs is important for substrate recognition. To investigate conformations of the NTA that could recognize substrates we performed replica exchange molecular dynamics simulations. Behavior at normal and stress temperatures of the dimeric building blocks of dodecameric HSPs from wheat (Ta16.9) and pea (Ps18.1) were compared because they display high sequence similarity, but Ps18.1 is more efficient in binding specific substrates. In our simulations, the NTAs of the dimer are flexible and dynamic; however, rather than exhibiting highly extended conformations they retain considerable ?-helical character and contacts with the conserved ?-crystallin domain (ACD). Network analysis and clustering methods reveal that there are two major conformational forms designated either "open" or "closed" based on the relative position of the two NTAs and their hydrophobic solvent accessible surface area. The equilibrium constant for the closed to open transition is significantly different for Ta16.9 and Ps18.1, with the latter showing more open conformations at elevated temperature correlated with its more effective chaperone activity. In addition, the Ps18.1 NTAs have more hydrophobic solvent accessible surface than those of Ta16.9. NTA hydrophobic patches are comparable in size to the area buried in many protein-protein interactions, which would enable sHSPs to bind early unfolding intermediates. Reduced interactions of the Ps18.1 NTAs with each other and with the ACD contribute to the differences in dynamics and hydrophobic surface area of the two sHSPs. These data support a major role for the conformational equilibrium of the NTA in substrate binding and indicate features of the NTA that contribute to sHSP chaperone efficiency.

Dataset Information

Molecular dynamics simulations using temperature-enhanced essential dynamics replica exchange.

Publications

Molecular dynamics simulations using temperature-enhanced essential dynamics replica exchange.

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