scholarly journals Chirality-Dependent Adsorption between Amphipathic Peptide and POPC Membrane

2019 ◽  
Vol 20 (19) ◽  
pp. 4760
Author(s):  
Ke Chen ◽  
Yuebiao Sheng ◽  
Jun Wang ◽  
Wei Wang
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Umbrella Sampling ◽  
Free Energy Barrier ◽  
Chiral Molecules ◽  
Local Interactions ◽  
Amphipathic Peptide ◽  
Slow Kinetics ◽  
Chiral Amino Acids ◽  
Free Energy Landscapes

The interactions between chiral molecules and cell membranes have attracted more and more attention in recent decades, due to their importance in molecular science and medical applications. It is observed that some peptides composed of different chiral amino acids may have distinct interactions with a membrane. How does the membrane exhibit a selective behavior related to the chirality of the peptides? Microscopically, the interactions between the peptides and the membrane are poorly understood. In this work, we study the interactions between an amphipathic peptide (C6) and POPC membrane with simulations. The kinetics and thermodynamics of peptide enantiomers during the adsorption to the membrane are characterized with direct simulations and umbrella sampling. It is observed that there are slow kinetics for the peptide composed of D-type amino acids. Along the observed pathways, the free energy landscapes are determined with umbrella sampling techniques. A free-energy barrier for the peptide composed of D-amino acids is observed, which is consistent with the kinetic observations. The results indicate the concurrent adsorption and rotation of the peptide helix. The local interactions between the peptides and the membrane are examined in detail, including the contact interactions between the peptides and the membrane, and the distributions of the lipids around the peptide. There are observable differences of the local interactions for the cases related to different peptide enantiomers. These results further demonstrate the importance of the rotation of peptide helix during the adsorption. More interestingly, all these kinetic differences between peptide enantiomers can be explained based on the conformations of the residue Trp and interactions between Trp and lipid molecules. These results give us a molecular understanding of the mechanism of the chirality-dependent peptide–membrane interactions, and may provide clues to designing systems which are sensitive to the chirality of membranes.

scholarly journals Probing remdesivir nucleotide analogue insertion to SARS-CoV-2 RNA dependent RNA polymerase in viral replication

2021 ◽  
Author(s):  
Moises Ernesto Romero ◽  
Chunhong Long ◽  
Daniel La Rocco ◽  
Anusha Mysore Keerthi ◽  
Dajun Xu ◽  
...  
Keyword(s):  
Free Energy ◽  
Rna Polymerase ◽  
Active Site ◽  
Energy Barrier ◽  
Umbrella Sampling ◽  
Dynamics Simulation ◽  
Free Energy Barrier ◽  
Base Stacking ◽  
Rna Dependent Rna Polymerase ◽  
Nucleotide Analogue

Remdesivir (RDV) prodrug can be metabolized into a triphosphate form nucleotide analogue (RDV-TP) to bind and insert into the active site of viral RNA dependent RNA polymerase (RdRp) to further interfere with the viral genome replication. In this work, we computationally studied how RDV-TP binds and inserts to the SARS-CoV-2 RdRp active site, in comparison with natural nucleotide substrate adenosine triphosphate (ATP). To do that, we first constructed atomic structural models of an initial binding complex (active site open) and a substrate insertion complex (active site closed), based on high-resolution cryo-EM structures determined recently for SARS-CoV-2 RdRp or non-structural protein (nsp) 12, in complex with accessory protein factors nsp7 and nsp8. By conducting all-atom molecular dynamics simulation with umbrella sampling strategies on the nucleotide insertion between the open and closed state RdRp complexes, our studies show that RDV-TP can bind comparatively stabilized to the viral RdRp active site, as it primarily forms base stacking with the template Uracil nucleotide (at +1), which is under freely fluctuations and supports a low free energy barrier of the RDV-TP insertion (~ 1.5 kcal/mol). In comparison, the corresponding natural substrate ATP binds to the RdRp active site in Watson-Crick base pairing with the template nt, and inserts into the active site with a medium low free energy barrier (~ 2.6 kcal/mol), when the fluctuations of the template nt are well quenched. The simulations also show that the initial base stacking of RDV-TP with the template can be particularly stabilized by motif B-N691, S682, and motif F-K500 with the sugar, base, and the template backbone, respectively. Although the RDV-TP insertion can be hindered by motif-F R555/R553 interaction with the triphosphate, the ATP insertion seems to be facilitated by such interactions. The inserted RDV-TP and ATP can be further distinguished by specific sugar interaction with motif B-T687 and motif-A D623, respectively.

scholarly journals Molecular Dynamics Simulations of the “Breathing” Phase Transformation of MOF Nanocrystallites

2019 ◽  
Author(s):  
Julian Keupp ◽  
Rochus Schmid
Keyword(s):  
Free Energy ◽  
Phase Transformation ◽  
Surface Effect ◽  
Umbrella Sampling ◽  
Distance Restraint ◽  
Free Energy Barrier ◽  
The One ◽  
Dynamics Simulations ◽  
The Impact ◽  
Closed Pore

One of the intriguing features of certain metal-organic frameworks (MOFs) is the large volume change upon external stimuli like pressure or guest molecule adsorption, referred to as “breathing”. This displacive phase transformation from an open to a closed pore has been investigated intensively by theoretical simulations within periodic boundary conditions (PBC). However, the actual free energy barriers for the transformation under real conditions and the impact of surface effects on it can only be studied beyond PBC for nanocrystallites. In this work, we used the first-principles parameterized forcefield MOF-FF to investigate the thermal- and pressure induced transformations for nanocrystallites of the pillared-layer DMOF-1 (Zn<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(bdc)<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(dabco); bdc: 1,4-benzenedicarboxylate; dabco: 1,4-diazabicyclo[2.2.2]octane) as a model system. By heating of prepared closed pore nanocrystallites of different size, a spontaneous opening is observed within a few tenth of picoseconds with an interface between the closed and open pore phase moving with a velocity of several 100 m/s<math><mrow><mrow><mi></mi> </mrow><mrow><mi></mi> </mrow> </mrow></math> through the system. The critical nucleation temperature for the opening transition raises with size. On the other hand, by forcing the closing transition with a distance restraint between paddle-wheel units placed on opposite edges of the crystallite, the free energy barrier can be determined by umbrella sampling. As expected, this barrier is substantially lower than the one determined for a concerted process under PBC. Interestingly, the barrier reduces with the size of the crystallite, indicating a hindering surface effect. The results demonstrate the need consider domain boundaries and surfaces, for example by simulations that go beyond PBC and to large system sizes in order to properly predict and describe first order phase transitions in MOFs.<div> </div>

scholarly journals Molecular Dynamics Simulations of the “Breathing” Phase Transformation of MOF Nanocrystallites

2019 ◽  
Author(s):  
Julian Keupp ◽  
Rochus Schmid
Keyword(s):  
Free Energy ◽  
Phase Transformation ◽  
Surface Effect ◽  
Umbrella Sampling ◽  
Distance Restraint ◽  
Free Energy Barrier ◽  
The One ◽  
Dynamics Simulations ◽  
The Impact ◽  
Closed Pore

One of the intriguing features of certain metal-organic frameworks (MOFs) is the large volume change upon external stimuli like pressure or guest molecule adsorption, referred to as “breathing”. This displacive phase transformation from an open to a closed pore has been investigated intensively by theoretical simulations within periodic boundary conditions (PBC). However, the actual free energy barriers for the transformation under real conditions and the impact of surface effects on it can only be studied beyond PBC for nanocrystallites. In this work, we used the first-principles parameterized forcefield MOF-FF to investigate the thermal- and pressure induced transformations for nanocrystallites of the pillared-layer DMOF-1 (Zn<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(bdc)<math> <mrow> <msub><mrow></mrow> <mrow><mn>2</mn> </mrow> </msub> </mrow></math>(dabco); bdc: 1,4-benzenedicarboxylate; dabco: 1,4-diazabicyclo[2.2.2]octane) as a model system. By heating of prepared closed pore nanocrystallites of different size, a spontaneous opening is observed within a few tenth of picoseconds with an interface between the closed and open pore phase moving with a velocity of several 100 m/s<math><mrow><mrow><mi></mi> </mrow><mrow><mi></mi> </mrow> </mrow></math> through the system. The critical nucleation temperature for the opening transition raises with size. On the other hand, by forcing the closing transition with a distance restraint between paddle-wheel units placed on opposite edges of the crystallite, the free energy barrier can be determined by umbrella sampling. As expected, this barrier is substantially lower than the one determined for a concerted process under PBC. Interestingly, the barrier reduces with the size of the crystallite, indicating a hindering surface effect. The results demonstrate the need consider domain boundaries and surfaces, for example by simulations that go beyond PBC and to large system sizes in order to properly predict and describe first order phase transitions in MOFs.<div> </div>

scholarly journals In silico Probing Ca2+ And Zn2+ Permeable Transmembrane 4Aβ1-42 Barrel

2020 ◽  
Vol 31 (1) ◽  
Author(s):  
Son Tung Ngo
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Umbrella Sampling ◽  
Free Energy Barrier ◽  
Aβ Oligomers ◽  
Aβ Peptides ◽  
Computational Approaches ◽  
Ions Transport ◽  
Ad Therapy ◽  
Numerous People

Alzheimer’s disease is known as one of the most popular forms of dementia affecting numerous people worldwide. The Amyloid beta (Aβ) peptides form to oligomeric conformations that cause the intracellular Ca2+ and Zn2+ abnormality leading to the death of neuron cells. The failure of AD therapy targeting Aβ oligomers probably caused by misunderstanding the ions transport through transmembrane Aβ (tmAβ) ion-like channel since Aβ oligomers transiently exist in a mixture order of Aβ oligomers. The high-resolution of tmAβ peptides are thus unavailable until the date. Fortunately, computational approaches are able to complement the missing experimental structures. The transmembrane 4Aβ1-42 (tm4Aβ1-42) barrel, one of the most neurotoxic elements, was thus predicted in the previous work. Therefore, in this context, the Ca2+/Zn2+ ions transport through the tm4Aβ1-42 barrel was investigated by using the fast pulling of ligand (FPL) and umbrella sampling (US) methods. Good consistent results were obtained implying that Ca2+ ion transport through tm4Aβ1-42 barrel with a lower free energy barrier compared with Zn2+ ion. The obtained results about Ca2+/Zn2+ transport across tmAβ1-42 barrel probably enhances the AD therapy

scholarly journals Free Energy Landscapes of Vesicle Fusion by Umbrella Sampling MD Simulations

2013 ◽  
Vol 104 (2) ◽  
pp. 92a ◽  
Author(s):  
Gregory Bubnis ◽  
H.J. Risselada ◽  
Helmut Grubmueller
Keyword(s):  
Free Energy ◽  
Md Simulations ◽  
Vesicle Fusion ◽  
Umbrella Sampling ◽  
Energy Landscapes ◽  
Free Energy Landscapes

scholarly journals Simulations of octapeptin–outer membrane interactions reveal conformational flexibility is linked to antimicrobial potency

2020 ◽  
Vol 295 (47) ◽  
pp. 15902-15912 ◽  
Author(s):  
Xukai Jiang ◽  
Kai Yang ◽  
Bing Yuan ◽  
Bin Gong ◽  
Lin Wan ◽  
...  
Keyword(s):  
Free Energy ◽  
Outer Membrane ◽  
Lipid Membranes ◽  
Energy Barrier ◽  
Lipid A ◽  
Umbrella Sampling ◽  
Fatty Acyl ◽  
Hydroxyl Group ◽  
Free Energy Barrier ◽  
Gram Negative

The octapeptins are lipopeptide antibiotics that are structurally similar to polymyxins yet retain activity against polymyxin-resistant Gram-negative pathogens, suggesting they might be used to treat recalcitrant infections. However, the basis of their unique activity is unclear because of the difficulty in generating high-resolution experimental data of the interaction of antimicrobial peptides with lipid membranes. To elucidate these structure–activity relationships, we employed all-atom molecular dynamics simulations with umbrella sampling to investigate the conformational and energetic landscape of octapeptins interacting with bacterial outer membrane (OM). Specifically, we examined the interaction of octapeptin C4 and FADDI-115, lacking a single hydroxyl group compared with octapeptin C4, with the lipid A–phosphoethanolamine modified OM of Acinetobacter baumannii. Octapeptin C4 and FADDI-115 both penetrated into the OM hydrophobic center but experienced different conformational transitions from an unfolded to a folded state that was highly dependent on the structural flexibility of their respective N-terminal fatty acyl groups. The additional hydroxyl group present in the fatty acyl group of octapeptin C4 resulted in the molecule becoming trapped in a semifolded state, leading to a higher free energy barrier for OM penetration. The free energy barrier for the translocation through the OM hydrophobic layer was ∼72 kcal/mol for octapeptin C4 and 62 kcal/mol for FADDI-115. Our results help to explain the lower antimicrobial activity previously observed for octapeptin C4 compared with FADDI-115 and more broadly improve our understanding of the structure–function relationships of octapeptins. These findings may facilitate the discovery of next-generation octapeptins against polymyxin-resistant Gram-negative 'superbugs.'

Determination of Base Flipping Free Energy Landscapes from Nonequilibrium Stratification

2019 ◽  
Author(s):  
Xiaohui Wang ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Sampling Technique ◽  
Umbrella Sampling ◽  
Energy Simulation ◽  
Nonlinear Dependence ◽  
Free Energy Landscape ◽  
Convergence Criterion ◽  
Base Flipping ◽  
Convergence Behavior

<p>Correct calculation of the variation of free energy upon base flipping is crucial in understanding the dynamics of DNA systems. The free energy landscape along the flipping pathway gives the thermodynamic stability and the flexibility of base-paired states. Although numerous free energy simulations are performed in the base flipping cases, no theoretically rigorous nonequilibrium techniques are devised and employed to investigate the thermodynamics of base flipping. In the current work, we report a general nonequilibrium stratification scheme for efficient calculation of the free energy landscape of base flipping in DNA duplex. We carefully monitor the convergence behavior of the equilibrium sampling based free energy simulation and the nonequilibrium stratification and determine the empirical length of time blocks required for converged sampling. Comparison between the performances of equilibrium umbrella sampling and nonequilibrium stratification is given. The results show that nonequilibrium free energy simulation is able to give similar accuracy and efficiency compared with the equilibrium enhanced sampling technique in the base flipping cases. We further test a convergence criterion we previously proposed and it comes out that the convergence behavior determined by this criterion agrees with those given by the time-invariant behavior of PMF and the nonlinear dependence of standard deviation on the sample size. </p>

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

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