Essential dynamics: foundation and applications

Daidone, Isabella; Amadei, Andrea

doi:10.1002/wcms.1099

Cited by 107 publications

(119 citation statements)

References 63 publications

(78 reference statements)

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“…According to essential dynamics (ED) approach (Amadei, Ceruso, & Di Nola, 1999;Amadei, Linssen, & Berendsen, 1993;Chan & Mulet, 1999;Daidone & Amadei, 2012) For the simulations of both tmRBP and ecRBP, only Cα atoms were comprise in the computation of the covariance matrices. The root mean square inner product (RMSIP) was compute to estimate the degree of overlap between the essential subspaces of the two simulated systems at both the same and different temperatures.…”

Section: Essential Dynamics Analysismentioning

confidence: 99%

Thermal stability and unfolding pathways of hyperthermophilic and mesophilic periplasmic binding proteins studied by molecular dynamics simulation

Chen

Wang

et al. 2016

Journal of Biomolecular Structure and Dynamics

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The ribose binding protein (RBP), a sugar-binding periplasmic protein, is involved in the transport and signaling processes in both prokaryotes and eukaryotes. Although several cellular and structural studies have been reported, a description of the thermostability of RBP at the molecular level remains elusive. Focused on the hyperthermophilic Thermoytoga maritima RBP (tmRBP) and mesophilic Escherichia coli homolog (ecRBP), we applied molecular dynamics simulations at four different temperatures (300, 380, 450, and 500 K) to obtain a deeper insight into the structural features responsible for the reduced thermostability of the ecRBP. The simulations results indicate that there are distinct structural differences in the unfolding pathway between the two homologs and the ecRBP unfolds faster than the hyperthermophilic homologs at certain temperatures in accordance with the lower thermal stability found experimentally. Essential dynamics analysis uncovers that the essential subspaces of ecRBP and tmRBP are non-overlapping and these two proteins show different directions of motion within the simulations trajectories. Such an understanding is required for designing efficient proteins with characteristics for a particular application.

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Section: Essential Dynamics Analysismentioning

confidence: 99%

Thermal stability and unfolding pathways of hyperthermophilic and mesophilic periplasmic binding proteins studied by molecular dynamics simulation

Chen

Wang

et al. 2016

Journal of Biomolecular Structure and Dynamics

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“…The Principal Component Analysis (PCA) [61] was performed with GROMACS using C α atoms coordinates of snapshots extracted from the production trajectory every 100 ps. The trajectories were then projected onto the PCs associated with the two largest eigenvalues (PC1 and PC2).…”

Section: Analysis Of MD Trajectoriesmentioning

confidence: 99%

Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil

Hashem

Tiberti

Fornili

2018

Biophysical Journal

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New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations. Author summaryCardiac myosin is a motor protein responsible for the contraction of the heart muscle. New strategies for the cure of heart diseases are currently being developed by using myosin modulators, which are small molecules that can interact with myosin and modify its activity. The advantage of this approach over traditional drugs is that by directly targeting cardiac myosin it is possible to have drugs with reduced side effects. Moreover, the availability of a spectrum of molecules to finely tune myosin to a desired level of activity opens the possibility to develop more precise and personalised drug therapies. In this work, we study a recently discovered activator of cardiac myosin, omecamtiv mecarbil, in order to understand its mechanism of action. In particular, we use Molecular Dynamics simulations to unravel the effects of the drug on myosin motions, which are closely related to its PLOS Computational Biology | https://doi

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“…Such a technique is based on the possibility to guide the sampling towards a target and to reject movements (in the conformational space) which are not in the desired direction. With respect to other enhancing sampling methodologies (for a brief overview on the subject, see for examples the review of Tai (Daidone & Amadei, 2012;Tai, 2004) and references therein), the advantages of the EDS technique are that the system moves along its own essential eigenvectors as provided by free (unbiased) molecular dynamics (MD) and no ad hoc terms are introduced in the Hamiltonian. Moreover, the contraction procedure guarantees -by construction -that the system goes from an initial state to a final state, being only slightly constrained.…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms of activation in CDK2

Bešker

Amadei

D’Abramo³

2013

Journal of Biomolecular Structure and Dynamics

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Cyclin-dependent kinases (CDKs) are enzymes involved in crucial cellular processes. Their biological activity is directly linked to their high conformational variability, which involves large protein conformational rearrangements. We present here the application of an enhancing sampling technique to the study of conformational transitions between the open and closed state of CDKs. The analysis of the conformational intermediates supports the idea that the process is regulated by two important protein regions, which sequentially rearrange in order to allow the protein to reach its final conformation. Furthermore, the two paths involve additional (minor) protein rearrangements which are specific to the paths. Our results show that our procedure can provide reasonable transition pathways between the two protein forms at a very reduced computational cost. The robustness and the simplicity of our approach make it of general application to describe virtually any macromolecular conformational transitions.

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Essential dynamics: foundation and applications

Cited by 107 publications

References 63 publications

Thermal stability and unfolding pathways of hyperthermophilic and mesophilic periplasmic binding proteins studied by molecular dynamics simulation

Thermal stability and unfolding pathways of hyperthermophilic and mesophilic periplasmic binding proteins studied by molecular dynamics simulation

Allosteric Modulation of Cardiac Myosin Dynamics by Omecamtiv Mecarbil

Molecular mechanisms of activation in CDK2

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