Electric-Field-Induced Protein Translocation via a Conformational Transition in SecDF: An MD Study

Ficici, Emel; Jeong, Daun; Andricioaei, Ioan

doi:10.1016/j.bpj.2017.04.034

Cited by 8 publications

(8 citation statements)

References 54 publications

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“…This results in reshaped local interactions and relative displacements between domains. Disruption of the secondary structure of S, particularly at the RBM, occurs under notoriously weaker EFs than those needed to produce significant changes in other proteins 26,28,32 . This suggests a possible causal link between structural vulnerability and affinity to ACE2.…”

Section: Discussionmentioning

confidence: 99%

“…It has been theoretically predicted and experimentally demonstrated that static and timedependent electric fields (EFs) are capable of inducing conformational changes [25][26][27][28][29][30] or even irreversible damage in proteins [31][32][33] . The fact that extremely intense EFs of strengths larger than 1Volt per nanometre (10 9 V m⁻¹) can denature entire proteins and even break chemical bonds is trivial and of little biological relevance.…”

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confidence: 99%

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The SARS-CoV-2 spike protein is vulnerable to moderate electric fields

et al. 2021

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Most of the ongoing projects aimed at the development of specific therapies and vaccines against COVID-19 use the SARS-CoV-2 spike (S) protein as the main target. The binding of the spike protein with the ACE2 receptor (ACE2) of the host cell constitutes the first and key step for virus entry. During this process, the receptor binding domain (RBD) of the S protein plays an essential role, since it contains the receptor binding motif (RBM), responsible for the docking to the receptor. So far, mostly biochemical methods are being tested in order to prevent binding of the virus to ACE2. Here we show, with the help of atomistic simulations, that external electric fields of easily achievable and moderate strengths can dramatically destabilise the S protein, inducing long-lasting structural damage. One striking field-induced conformational change occurs at the level of the recognition loop L3 of the RBD where two parallel beta sheets, believed to be responsible for a high affinity to ACE2, undergo a change into an unstructured coil, which exhibits almost no binding possibilities to the ACE2 receptor. We also show that these severe structural changes upon electric-field application also occur in the mutant RBDs corresponding to the variants of concern (VOC) B.1.1.7 (UK), B.1.351 (South Africa) and P.1 (Brazil). Remarkably, while the structural flexibility of S allows the virus to improve its probability of entering the cell, it is also the origin of the surprising vulnerability of S upon application of electric fields of strengths at least two orders of magnitude smaller than those required for damaging most proteins. Our findings suggest the existence of a clean physical method to weaken the SARS-CoV-2 virus without further biochemical processing. Moreover, the effect could be used for infection prevention purposes and also to develop technologies for in-vitro structural manipulation of S. Since the method is largely unspecific, it can be suitable for application to other mutations in S, to other proteins of SARS-CoV-2 and in general to membrane proteins of other virus types.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The SARS-CoV-2 spike protein is vulnerable to moderate electric fields

et al. 2021

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“…SecDF is thought to use the proton gradient for both the conformation switch and binding-release cycles (Tsukazaki et al 2011). This mechanism was supported by MD simulations (Ficici et al 2017), which concluded that the P1 head movement is regulated by the transmembrane potential. The barrier for such transition is lowered in the presence of the transmembrane potential Δψ.…”

Section: Introductionmentioning

confidence: 74%

Driving Forces of Translocation Through Bacterial Translocon SecYEG

et al. 2018

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This review focusses on the energetics of protein translocation via the Sec translocation machinery. First we complement structural data about SecYEG’s conformational rearrangements by insight obtained from functional assays. These include measurements of SecYEG permeability that allow assessment of channel gating by ligand binding and membrane voltage. Second we will discuss the power stroke and Brownian ratcheting models of substrate translocation and the role that the two models assign to the putative driving forces: (i) ATP (SecA) and GTP (ribosome) hydrolysis, (ii) interaction with accessory proteins, (iii) membrane partitioning and folding, (iv) proton motive force (PMF), and (v) entropic contributions. Our analysis underlines how important energized membranes are for unravelling the translocation mechanism in future experiments.

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“…Living systems naturally produce weak electric fields. Electrostatic forces, as long-range interactions, play a crucial role in defining the structure and properties of proteins [ 18 , 19 , 20 ]. Experimental studies have been carried out to understand the effect of an external environment on the protein properties, and even to explore the possibilities to control protein process via surface-enhanced resonance Raman spectroscopy (SERRS) [ 21 ], quartz crystal vibrational analysis (QCV) [ 22 ], the measurement of electrical double layer capacitance [ 23 , 24 ], etc.…”

Section: Introductionmentioning

confidence: 99%

Effects of an Electric Field on the Conformational Transition of the Protein: A Molecular Dynamics Simulation Study

et al. 2019

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The effect of the electric field on the conformational properties of the protein 1BBL was investigated by molecular dynamics simulations. Our simulation results clearly capture the structural transitions of the protein sample from helix to turn or random coil conformation induced by the increasing strength of the electric field. During our analysis, we found that the conformational stability is weakened, and the protein sample is stretched as an unfolded structure when it was exposed in a sufficiently high electric field. The characteristic time when the jump occurs in the time evolution curves of root mean square deviation (RMSD) and radius of gyration Rg decreases with increasing electric strength, which demonstrates the rapidly conformational transition that occurs. The number of intra-protein hydrogen bonds, which is the key factor for stabilizing the protein structure, is related to the overall size of the protein. The value of the dipole moment and characteristic time are both influenced by the strength, but are independent of the direction of the external field. The protein sample becomes rotated with the electric field direction. These conclusions provide a theoretical realization of understanding the protein conformational transition in an electric field and the guidance for anticipative applications.

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Electric-Field-Induced Protein Translocation via a Conformational Transition in SecDF: An MD Study

Cited by 8 publications

References 54 publications

The SARS-CoV-2 spike protein is vulnerable to moderate electric fields

The SARS-CoV-2 spike protein is vulnerable to moderate electric fields

Driving Forces of Translocation Through Bacterial Translocon SecYEG

Effects of an Electric Field on the Conformational Transition of the Protein: A Molecular Dynamics Simulation Study

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