Effect of external pulling forces on the length distribution of peptides

Batchelor, Matthew; Gowdy, James; Paci, Emanuele

doi:10.1016/j.bbagen.2014.09.019

Cited by 4 publications

(9 citation statements)

References 60 publications

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“…This suggests that formation of more salt bridges may not be the major contributor to a more stable helix for these polyampholyte motifs. As part of a previous study, 15 we modeled some related but shorter (10 residue) polyampholyte sequences using the CHARMM19 force field and FACTS implicit solvation and compared with helicities available from the literature. 31 Those simulations did not show the differences in helicity between the E 4 K 4 and E 4 R 4 motifs observed in experimental studies.…”

Section: ■ Resultsmentioning

confidence: 99%

“…Some intriguing hypotheses on the origin of the extraordinary properties of helical polyampholyte sequences have been previously formulated, based on thermodynamic and kinetic properties of simulations of computational models. [14][15][16] Computational models are limited by the quality of force fields. Traditional force fields were developed to stabilize known protein structures.…”

Section: Introductionmentioning

confidence: 99%

“…In simulations with different force fields we observed a peculiar response to mechanical force, namely the application of a force does not increase the rate of unfolding as for structured proteins, but causes a progressive elongation to which the helix responds with an approximately constant recoiling force. [14][15] Here we report thermodynamic properties estimated using the OPLS/ABSINTH 19 force-field and replica-exchange Monte Carlo simulations for a wide range of peptide sequences, each sixteen residues in length, and linked, where possible, to ensemble average properties known from experimental studies.…”

Section: Introductionmentioning

confidence: 99%

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Helical Polyampholyte Sequences Have Unique Thermodynamic Properties

Batchelor

Paci

2018

J. Phys. Chem. B

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Helices are the most common structural pattern observed in structured proteins. Polypeptide sequences that form helices in isolation have been identified and extensively studied. These are generally rich in alanine, the amino acid with strongest helical propensity. Insertion of charged or polar amino acids has been shown to be necessary to make alanine-rich peptides soluble, and sometimes even increase the helicity of the peptides. More recently sequences that contain mostly charged residues (E-R/K rich) have been found in naturally occurring proteins that are highly helical, soluble and extended regardless their length. Artificial sequences composed mostly or exclusively of charged amino acids have been designed that are also highly helical, depending on the specific pattern of oppositely charged residues. Here we explore the thermodynamic properties of a number of 16-residue long peptides with varying helical propensity by performing equilibrium simulations in a broad range of temperatures. We observe quantitative differences in the peptides' helical propensities that can be related to qualitative differences in the free energy landscape, depending on the ampholytic patterns in the sequence. The results provide hints on how the specific physical properties of naturally occurring long sequences with similar patterns of charged residues may relate to their biological function.

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Section: ■ Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Helical Polyampholyte Sequences Have Unique Thermodynamic Properties

Batchelor

Paci

2018

J. Phys. Chem. B

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“…The total work was calculated as the cumulative work over all steps P n 0 FðiÞ dðiÞ. It should be noted that the pulling work can be significantly overestimated because the pulling was done over a very limited timescale (20 ns) (29)(30)(31). For an estimate of the free energy, methods such as umbrella sampling simulations could be utilized (32).…”

Section: Steered Molecular Dynamics Simulation Of the Separation Of S2 Domain From S1 Subunitmentioning

confidence: 99%

Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of Spike protein S1 and S2

Buck

2021

Biophysical Journal

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The cell surface receptor Neuropilin-1 (Nrp1) was recently identified as a host factor for SARS-CoV-2 entry. Spike protein of SARS-CoV-2 is cleaved into two segments, the S1 (res. 1-685) and the S2 (res. 686-1273) domain by furin protease. Nrp1 predominantly binds to the C-terminal RRAR motif (res. 682-685) of the S1 domain. In this study, we firstly modeled the association of a Nrp1 protein (consisting of domains a2-b1-b2) with the Spike protein. Next, we studied the separation of S2 from the S1 domain, with and without Nrp1 bound, by utilizing molecular dynamics pulling simulations. During the separation, Nrp1 stabilizes the S1 C-terminal region (res. 640-685) and thereby assists the detachment of S2 N-terminal region (res. 686-700). Without Nrp1 bound, S1 tends to become stretched and thus the bound Nrp1 stimulates the earlier separation of S2 from the S1 domain. The liberated S2 domain is known to mediate the fusion of virus and host membranes, thus Nrp1 likely increases virus infectivity by facilitating the S1/S2 separation. We further analyzed the possible topological structure of the SARS-CoV-2 Spike protein when bound with Nrp1 and ACE2. Understanding of such a Nrp1-assisted viral infection opens the gate for the generation of protein-protein inhibitors, such as antibodies, which could attenuate the infection mechanism and protect certain cells in a future Nrp1:ACE2 targeted combination therapy.

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“…Trapping in metastable states is one reason behind inefficient sampling, and Caflisch et al [4] show that exploration of phase space is enhanced with the help of a simulation protocol that terminates and restarts trajectories in a more productive direction if they are found to be re-sampling overlapping regions of phase space. Paci et al [5] use external forces to increase sampling of otherwise undersampled peptide conformations (either very extended or more compressed). Length distributions can be measured experimentally, and the force enhanced sampling is shown to agree with experiment for a series of short peptides of varying amino acid composition.…”

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confidence: 99%