Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules

Hamelberg, Donald; Marcus, John; McCammon, J. Andrew

doi:10.1063/1.1755656

Cited by 1,369 publications

(1,557 citation statements)

References 28 publications

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“…23,26 To calculate the statistical inefficiency, s, first, the trajectories are broken down into a series of n b blocks of size t b . The average value of the property A (in this work A is the potential energy) for each block is given by (12) As the number of steps t b in each block increases, the block averages become increasingly uncorrelated. Besides, the variance of the block averages, σ 2 (〈A〉 b ), become inversely proportional to n b and is calculated as (13) where 〈A〉 total is the average taken during the entire simulation.…”

Section: Resultsmentioning

confidence: 99%

On the Application of Accelerated Molecular Dynamics to Liquid Water Simulations

2006

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Our group recently proposed a robust bias potential function that can be used in an efficient all-atom accelerated molecular dynamics approach to simulate the transition of high energy barriers without any advance knowledge of the potential energy landscape. The main idea is to modify the potentialenergy surface by adding a bias, or boost, potential in regions close to the local minima, such that all transitions rates are increased. By applying the accelerated MD simulation method to liquid water, we observed that this new simulation technique accelerates the molecular motions without losing its microscopic structure and equilibrium properties. Our results showed that the application of small boost energy on the potential energy surface significantly reduces the statistical inefficiency of the simulation while keeping all the other calculated properties unchanged. On the other hand, although aggressive acceleration of the dynamic simulation increases the self-diffusion coefficient of water molecules greatly and dramatically reduces the correlation time of the simulation, configurations representative of the true structure of liquid water are poorly sampled. Our results also showed the strength and robustness of this simulation technique, which confirm this approach as a very useful and promising tool to extend the time scale of the all-atom simulations of biological system with explicit solvent models. However, we should keep in mind that there is a compromise between the strength of the boost applied in the simulation and the reproduction of the ensemble average properties.

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Section: Resultsmentioning

confidence: 99%

On the Application of Accelerated Molecular Dynamics to Liquid Water Simulations

2006

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“…Activated and long-time processes can also be studied by using high-temperature simulations, 9 aggregate dynamics, 10 enhanced sampling by MC/MD, [11][12][13][14] replica dynamics, 15,16 free-energy calculations, 17-19 path sampling [20][21][22] or the stochastic path approach. 23 All these methodologies are based on different approximations and address varied problems (see, for example, ref 24).…”

Section: Introductionmentioning

confidence: 99%

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Arora

Schlick

2005

J. Phys. Chem. B

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The closing conformational transition of wild-type polymerase bound to DNA template/primer before the chemical step (nucleotidyl transfer reaction) is simulated using the stochastic difference equation (in length version, "SDEL") algorithm that approximates long-time dynamics. The order of the events and the intermediate states during pol 's closing pathway are identified and compared to a separate study of pol using transition path sampling (TPS) (Radhakrishnan, R.; Schlick, T. Proc. Natl. Acad. Sci. USA 2004, 101, 5970-5975). Results highlight the cooperative and subtle conformational changes in the pol active site upon binding the correct substrate that may help explain DNA replication and repair fidelity. These changes involve key residues that differentiate the open from the closed conformation (Asp192, Arg258, Phe272), as well as residues contacting the DNA template/primer strand near the active site (Tyr271, Arg283, Thr292, Tyr296) and residues contacting the and γ phosphates of the incoming nucleotide (Ser180, Arg183, Gly189). This study compliments experimental observations by providing detailed atomistic views of the intermediates along the polymerase closing pathway and by suggesting additional key residues that regulate events prior to or during the chemical reaction. We also show general agreement between two sampling methods (the stochastic difference equation and transition path sampling) and identify methodological challenges involved in the former method relevant to large-scale biomolecular applications. Specifically, SDEL is very quick relative to TPS for obtaining an approximate path of medium resolution and providing qualitative information on the sequence of events; however, associated free energies are likely very costly to obtain because this will require both successful further refinement of the path segments close to the bottlenecks and large computational time.

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“…The classical MD simulations have been carried out to extract the average potential and the average dihedral energies, required by the aMD technique, 37 to modify the potential energy landscape. The aMD technique permits, due to the introduction of a bias potential, access to a large conformational space that cannot be normally accessed by classical MD.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…3,23,24,36 The computational and experimental data presented here indicate that the system is able to form a stable triple helix at pH 5.0, while at pH 8.0 there is no presence of the triple-and even of the double-helical structures. Two accelerated MD (aMD) simulations 37 (500 ns each) of the system, having protonated or unprotonated cytosines mimicking the pH 5.0 and 8.0 conditions, unravelled the atomistic detail of the folded to unfolded transition characterizing the two-state switching mechanism. The present study sets the basis for combined use of experimental and computational approaches to understand the mechanism of novel and efficient nanodevices to be included in complex nanosystems.…”

Section: ■ Introductionmentioning

confidence: 99%

Simulative and Experimental Characterization of a pH-Dependent Clamp-like DNA Triple-Helix Nanoswitch

et al. 2017

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Here we couple experimental and simulative techniques to characterize the structural/dynamical behavior of a pH-triggered switching mechanism based on the formation of a parallel DNA triple helix. Fluorescent data demonstrate the ability of this structure to reversibly switch between two states upon pH changes. Two accelerated, half microsecond, MD simulations of the system having protonated or unprotonated cytosines, mimicking the pH 5.0 and 8.0 conditions, highlight the importance of the Hoogsteen interactions in stabilizing the system, finely depicting the time-dependent disruption of the hydrogen bond network. Urea-unfolding experiments and MM/ GBSA calculations converge in indicating a stabilization energy at pH 5.0, 2-fold higher than that observed at pH 8.0. These results validate the pH-controlled behavior of the designed structure and suggest that simulative approaches can be successfully coupled with experimental data to characterize responsive DNA-based nanodevices. ■ INTRODUCTIONDNA nanotechnology allows us to design and engineer smart nanomaterials and nanodevices using synthetic DNA sequences. 1−6 For example, current methodologies and synthetic strategies, such as DNA tiles, origami, or supramolecular assembly, allowed the production of complex nanostructures of different shapes and dimensions. 7−11 The unparalleled versatility of these approaches allows precise positioning of molecule-responsive switching elements in specific locations of DNA nanostructures, leading to the construction of more complex functional nanodevices. 12−14 Similarly, enzyme−DNA nanostructures have been demonstrated to enhance enzyme catalytic activity and stability. 15 DNA motifs that rely on noncanonical DNA interactions, such as G-quadruplex, triplex, i-motif, hairpin, and aptamers, can be used to design such nanodevices due to their dynamic-responsive behavior toward chemical and environmental stimuli. 16,17 These responsive units often respond to specific chemical inputs through a bindinginduced conformational change mechanism that leads to a measurable output or function. The efficiency of this class of responsive nanodevices strongly depends on the designed structure-switching mechanism that controls their activity or functionality. Therefore, there is an urgent need to understand the energies involved in these responsive systems and the relationship between their structure and dynamics. 16 Among such functional DNA nanodevices, those based on the triple-helix motif are attracting interest for their strong and programmable pH dependence. 18−20 By rationally incorporating triplex-forming portions into DNA nanodevices, it is possible to trigger conformational changes and functions using pH as a chemical input. 21−24 Despite the fair amount of knowledge of the basic design principles and mechanism of action of triplex-based nanodevices, no reports describing the connection between their structural and dynamical properties are available. Toward this aim, simulative approaches represent valuable tools to shed ...

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Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules

Cited by 1,369 publications

References 28 publications

On the Application of Accelerated Molecular Dynamics to Liquid Water Simulations

On the Application of Accelerated Molecular Dynamics to Liquid Water Simulations

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Simulative and Experimental Characterization of a pH-Dependent Clamp-like DNA Triple-Helix Nanoswitch

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