Computer Modeling of Force-Induced Titin Domain Unfolding

Lü, Hui; Krammer, André; Isralewitz, Barry; Vogel, Viola; Schulten, Klaus

doi:10.1007/978-1-4615-4267-4_9

Cited by 23 publications

(20 citation statements)

References 45 publications

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“…This results in the much larger loading rates used in our simulations to enable the completion of the unfolding in the nano-second time scale than that used in the experiments (almost 10 8 times larger in our simulations). Similar phenomena have also been observed in the experimental and simulated force-induced unfolding of other protein domains such as titin [25], [38]. Our simulations revealed the detailed conformational changes of Ca 2+ -loaded CaM unfolding at the atomistic-level, and it is concluded that the two peak forces observed in both AFM experiments and our simulations should result in the conquering of the interactions between the two EF-hands motif in either domain, including the backbone hydrogen bond of EFβ-scaffold and the direct contact of the two motifs.…”

Section: Discussionsupporting

confidence: 78%

The Ca2+ Influence on Calmodulin Unfolding Pathway: A Steered Molecular Dynamics Simulation Study

Zhang

Lou

2012

PLoS ONE

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The force-induced unfolding of calmodulin (CaM) was investigated at atomistic details with steered molecular dynamics. The two isolated CaM domains as well as the full-length CaM were simulated in N-C-terminal pulling scheme, and the isolated N-lobe of CaM was studied specially in two other pulling schemes to test the effect of pulling direction and compare with relevant experiments. Both Ca2+-loaded CaM and Ca2+-free CaM were considered in order to define the Ca2+ influence to the CaM unfolding. The results reveal that the Ca2+ significantly affects the stability and unfolding behaviors of both the isolated CaM domains and the full-length CaM. In Ca2+-loaded CaM, N-terminal domain unfolds in priori to the C-terminal domain. But in Ca2+-free CaM, the unfolding order changes, and C-terminal domain unfolds first. The force-extension curves of CaM unfolding indicate that the major unfolding barrier comes from conquering the interaction of two EF-hand motifs in both N- and C- terminal domains. Our results provide the atomistic-level insights in the force-induced CaM unfolding and explain the observation in recent AFM experiments.

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Section: Discussionsupporting

confidence: 78%

The Ca2+ Influence on Calmodulin Unfolding Pathway: A Steered Molecular Dynamics Simulation Study

Zhang

Lou

2012

PLoS ONE

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“…Nevertheless, key insights into molecular behavior of bulky proteins like Titin that are commonly known to be mutated in DCM have been achieved by MD simulations (Herman et al, 2012). An earlier MD study of Titin wherein, single Ig domains of Titin were stretched reported sequential unfolding of Ig domains corroborating experiments (Lu et al, 1998, 2000; Gao et al, 2002). A recent study of Titin examined the hydrophobic core region of the protein associated with a DCM mutation V54M and reported destabilization of transition from bend to coil in secondary structure of Titin and reduced affinity to Z-disc protein T-cap/telethonin (Thirumal Kumar et al, 2016).…”

Section: Insights and Challenges From Molecular Modeling Of Regulatorsupporting

confidence: 65%

Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants—Genotype to Cellular Phenotype

et al. 2017

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Dilated Cardiomyopathy (DCM) is a leading cause of sudden cardiac death characterized by impaired pump function and dilatation of cardiac ventricles. In this review we discuss various in silico approaches to elucidating the mechanisms of genetic mutations leading to DCM. The approaches covered in this review focus on bridging the spatial and temporal gaps that exist between molecular and cellular processes. Mutations in sarcomeric regulatory thin filament proteins such as the troponin complex (cTn) and Tropomyosin (Tm) have been associated with DCM. Despite the experimentally-observed myofilament measures of contractility in the case of these mutations, the mechanisms by which the underlying molecular changes and protein interactions scale up to organ failure by these mutations remains elusive. The review highlights multi-scale modeling approaches and their applicability to study the effects of sarcomeric gene mutations in-silico. We discuss some of the insights that can be gained from computational models of cardiac biomechanics when scaling from molecular states to cellular level.

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“…The affected atoms are specified through a flag in the molecular coordinates (PDB) file, and the force vector is specified in the NAMD configuration. Intermediates found through constant-force SMD simulations may be modeled using the theory of mean first passage times for a barrier-crossing event [73,74]. Typical applied forces range from tens to a thousand picoNewtons (pN) [75].…”

Section: Steered and Interactive Molecular Dynamicsmentioning

confidence: 99%

Scalable molecular dynamics with NAMD

et al. 2005

Self Cite

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NAMD is a parallel molecular dynamics code designed for high-performance simulation of large biomolecular systems. NAMD scales to hundreds of processors on high-end parallel platforms, as well as tens of processors on low-cost commodity clusters, and also runs on individual desktop and laptop computers. NAMD works with AMBER and CHARMM potential functions, parameters, and file formats. This paper, directed to novices as well as experts, first introduces concepts and methods used in the NAMD program, describing the classical molecular dynamics force field, equations of motion, and integration methods along with the efficient electrostatics evaluation algorithms employed and temperature and pressure controls used. Features for steering the simulation across barriers and for calculating both alchemical and conformational free energy differences are presented. The motivations for and a roadmap to the internal design of NAMD, implemented in C++ and based on Charm++ parallel objects, are outlined. The factors affecting the serial and parallel performance of a simulation are discussed. Next, typical NAMD use is illustrated with representative applications to a small, a medium, and a large biomolecular system, highlighting particular features of NAMD, e.g., the Tcl scripting language. Finally, the paper provides a list of the key features of NAMD and discusses the benefits of combining NAMD with the molecular graphics/sequence analysis software VMD and the grid computing/collaboratory software BioCoRE. NAMD is distributed free of charge with source code at www.ks.uiuc.edu.

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Computer Modeling of Force-Induced Titin Domain Unfolding

Cited by 23 publications

References 45 publications

The Ca2+ Influence on Calmodulin Unfolding Pathway: A Steered Molecular Dynamics Simulation Study

The Ca2+ Influence on Calmodulin Unfolding Pathway: A Steered Molecular Dynamics Simulation Study

Insights and Challenges of Multi-Scale Modeling of Sarcomere Mechanics in cTn and Tm DCM Mutants—Genotype to Cellular Phenotype

Scalable molecular dynamics with NAMD

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