Pulling out a peptide chain from β-sheet crystallite: Propagation of instability of H-bonds under shear force

Anti-parallel β-sheet crystallite as the main component of silk fibroin has attracted much attention due to its superior mechanical properties. In this study, we examine the processes of pulling a peptide chain from β-sheet crystallite using steered molecular dynamics simulations to investigate the rupture behavior of the crystallite. We show that the failure of β-sheet crystallite was accompanied by a propagation of instability of hydrogen-bonds （H-bonds） in the crystallite. In addition, we find that there is an optimum size of the crystallite at which the H-bonds can work cooperatively to achieve the highest shear strength. In addition, we find that the stiffness of loading device and the loading rates have significant effects on the rupture behavior of β-sheet crystallite. The stiff loading device facilitates the rebinding of the Hbond network in the stick-slip motion between the chains, while the soft one suppresses it. Moreover, the rupture force of β-sheet crystallites decreases with loading rate. Particularly, when the loading rate decreases to a critical value, the rupture force of the β-sheet crystallite becomes independent of the loading rates. This study provides atomistic details of rupture behaviors of β-sheet crystallite, and, therefore, sheds valuable light on the underlying mechanism of the superior mechanical properties of silk fibroin.

Free energy calculation of single molecular interaction using Jarzynski's identity method:the case of HIV-1 protease inhibitor system

Jarzynski＇ identity （JI） method was suggested a promising tool for reconstructing free energy landscape of biomolecular interactions in numerical simulations and ex- periments. However, JI method has not yet been well tested in complex systems such as ligand-receptor molecular pairs. In this paper, we applied a huge number of steered molec- ular dynamics （SMD） simulations to dissociate the protease of human immunodeficiency type I virus （HIV-1 protease） and its inhibitors. We showed that because of intrinsic com- plexity of the ligand-receptor system, the energy barrier pre- dicted by JI method at high pulling rates is much higher than experimental results. However, with a slower pulling rate and fewer switch times of simulations, the predictions of JI method can approach to the experiments. These results sug- gested that the JI method is more appropriate for reconstruct- ing free energy landscape using the data taken from experi- ments, since the pulling rates used in experiments are often much slower than those in SMD simulations. Furthermore, we showed that a higher loading stiffness can produce higher precision of calculation of energy landscape because it yields a lower mean value and narrower bandwidth of work distri- bution in SMD simulations.

Computational Determination of the Binding Mode of α-Conotoxin to Nicotinic Acetylcholine Receptor

Abstract Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based on their targets. The a-conotoxins selectively inhibit the current of the nicotinic acetylcholine receptors. Because of their unique selectivity towards distinct nAChR subtypes, a-conotoxins become valuable tools in nAChR study. In addition to the X-ray structures of a-conotoxins in complex with acetyleholine-binding protein, a homolog of the nAChR ligand-binding domain, the high-resolution crystal structures of the extracellular domain of the al and a9 subunits are also obtained. Such structures not only revealed the details of the configuration of nAChR, but also provided higher sequence identity templates for modeling the binding modes of a-conotoxins to nAChR. This mini-review summarizes recent modeling studies for the determination of the binding modes of a-conotoxins to nAChR. As there are not crystal structures of the nAChR in complex with conotoxins, computational modeling in combination of mutagenesis data is expected to reveal the molecular recognition mechanisms that govern the interactions between a-conotoxins and nAChR at molecular level. An accurate determination of the binding modes of a-conotoxins on AChRs allows rational design of a-conotoxin analogues with improved potency or selectivity to nAChRs.

Rotational Mechanism of Ammonium Ion in Water and Methanol

Dynamics of ammonium and ammonia in solutions is closely related to the metabolism of arnrnoniac compounds, therefore plays an important role in various biological processes. NMR measurements indicated that the reorientation dynamics of NH4＋ is faster in its aqueous solution than in rnethanol, which deviates from the Stokes-Einstein-Debye rule since water has higher viscosity than methanol. To address this intriguing issue, we herein study the reorientation dynamics of ammonium ion in both solutions using numerical simulation and an extended cyclic Markov chain model. An evident decoupling between translation and ro- tation of methanol is observed in simulation, which results in the deviation of reorientation from the Stokes-Einstein-Debye rule. Slower hydrogen bond （HB） switchings of ammonium with rnethanol comparing to that with water, due to the steric effect of the rnethyl group, remarkably retards the jump rotation of ammonium. The observations herein provide useful insights into the dynamic behavior of ammonium in the heterogeneous environments including the protein surface or protein channels.

Molecular dynamics simulation of surface melting behaviours of the V(110) plane

The modified analytic embedded-atom method and molecular dynamics simulations are applied to the investigation of the surface premelting and melting behaviours of the V（110） plane by calculating the interlayer relaxation, the layer structure factor and atomic snapshots in this paper. The results obtained indicate that the premelting phenomenon occurs on the V（110） surface at about 1800K and then a liquid-like layer, which approximately keeps the same thickness up to 2020K, emerges on it. We discover that the temperature 2020K the V（110） surface starts to melt and is in a completely disordered state at the temperature of 2140K under the melting point for the bulk vanadium.

EFFECT OF TEMPERATURE ON DISLOCATION EMISSION FROM CRACK TIP FOR BCC METAL MO

The effect of thermally activated energy on the dislocationemission from a crack tip in BCC metal Mo is simulated in this paper.Based on the correlative reference model on which the flexi- bledisplacement boundary scheme is introduced naturally, the simulationshows that as temperature in creases the critical stress intensityfactor for the first dislocation emission will decrease and the totalnumber of emitted dislocations increase for the same external load.The dislocation velocity and exten- sive distance among partialdislocations are not sensitive to temperature.

Ionic liquids inhibit the dynamic transition fromα-helices toβ-sheets in peptides

Abnormalities in the transition betweenα-helices andβ-sheets(α-βtransition)may lead to devastating neurodegenerative diseases,such as Parkinson's syndrome and Alzheimer's disease.Ionic liquids(ILs)are potential drugs for targeted therapies against these diseases because of their excellent bioactivity and designability of ILs.However,the mechanism through which ILs regulate the aα-βtransition remains unclear.Herein,a combination of GPU-accelerated microsecond molecular dynamics simulations,correlation analysis,and machine learning was used to probe the dynamicalα-βtransition process induced by ILs of 1-alkyl-3-methylimidazolium chloride([C_(n)mim]cl)and its molecular mechanism.Interestingly,the cation of [C_(n)mim]+in ILs can spontaneously insert into the peptides as free ions(n≤10)and clusters(n≥11).Such insertion can significantly inhibit theα-β,transition and the inhibiting ability for the clusters is more significant than that of free ions,where[Ciomim]+and[C_(12)mim]+can reduce the maximumβ-sheet content of the peptide by 18.5% and 44.9%,respectively.Furthermore,the correlation analysis and machine learning method were used to develop a predictive model accounting for the influencing factors on theα-βtransition,which could accurately predict the effect of ILs on theα-βtransition.Overall,these quantitative results may not only deepen the understanding of the role of ILs in theα-βtransition but also guide the development of the IL-based treatments for related diseases.

Nanoscale inhibition of polymorphic and ambidextrous lAPP amyloid aggregation with small molecules

Understanding how small molecules interface with amyloid fibrils at the nanoscale is of importance for developing therapeutic treatments against amyloid-based diseases. Here, we show for the first time that human islet amyloid polypeptides （LAPP） in the fibrillar form are polymorphic, ambidextrous, and possess multiple periodicities. Upon interfacing with the small molecule epigallocatechin gallate （EGCG）, IAPP aggregation was rendered off-pathway and assumed a form with soft and disordered clusters, while mature IAPP fibrils displayed kinks and branching but conserved the twisted fibril morphology. These nanoscale phenomena resulted from competitive interactions between EGCG and the IAPP amyloidogenic region, as well as end capping of the fibrils by the small molecule. This information is crucial in delineating IAPP toxicity implicated in type 2 diabetes and for developing new inhibitors against amyloidogenesis.

Atomistic characterization of binding modes and affinity of peptide inhibitors to amyloid-β protein

Abstract The aggregation of amyloid β-protein （Aβ） is tightly linked to the pathogenesis of Alzheimer＇s disease. Previous studies have found that three peptide inhibitors （i.e., KLVFF, VVIA, and LPFFD） can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. How- ever, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area （MM/PBSA） analysis, we examined the effect of three peptide inhibitors （KLVFF, VVIA, and LPFFD） on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modifica- tion and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.

A Simple and Effective Boundary Model in Nonequilibrium Molecular Dynamics Method

Abstract We propose a simple and effective boundary model in a nonequilibrium molecular dynamics （NEMD） simulation to study the out-of-equilibrium dynamics of polymer fluids. The present boundary model can effectively weaken the depletion effect and the slip effect near the boundary, and remove the unwanted heat instantly. The validity of the boundary model is checked by investigating the flow behavior of dilute polymer solution driven by an external force. Reasonable density distributions of both polymer and solvent particles, velocity profiles of the solvent and temperature profiles of the system are obtained. Furthermore, the studied polymer chain shows a cross-streaming migration towards center of the tube, which is consistent with that predicted in previous literatures. These numerical results give powerful evidences for the validity of the present boundary model. Besides, the boundary model can also be used in other flows in addition to the Poiseuille flow.

Molecular dynamics and principal components of potassium binding with human telomeric intra-molecular G-quadruplex

Telomere assumes intra-molecular G-quadruplex that is a significant drug target for inhibiting telomerase main- tenance of telomeres in cancer. Metal cations have been recognized as playing important roles in stabilizing G-quadruplex, but their binding processes to human telomeric G-quadruplex remain uncharacterized. To in- vestigate the detailed binding procedures, molecular dynamics simulations were conducted on the hybrid [3 ＋ 1] form-one human telomeric intra-molecular G-quadruplex. We show here that the binding of a potas- sium ion to a G-tetrad core is mediated by two alternative pathways. Principal component analysis illustrated the dominant concerted motions of G-quadruplex occurred at the loop domains. MM-PBSA calculations revealed that binding was energetically favorable and driven by the electrostatic interactions. The lower binding site was found more constructive favorable for binding. Our data provide useful information on a potassium-mediated stable structure of human telomeric intra-molecular G-quadruplex, implicating in ion disorder associated conformationa｜ changes and targeted drug design.

Binding and conformation of dendrimer-based drug delivery systems:a molecular dynamics study

All atomistic molecular dynamics simulations were performed on poly （amidoamine） （PAMAM） dendrimers that compound non-covalently with anticancer drug molecules including DOX, MTX, CE6, and SN38. The binding energies as well as their associated interaction energies and deformation energies were combined to evaluate the relative binding strength among drug, PAMAM, and PEG chains. We find that the deformation of dendrimers due to drug loading plays a crucial role in the drug binding. It is energetically favorable for the drug molecules to bind with PAMAM while the drugs bind with PEG metastable chains via kinetic confinement. Surface PEGylation helps dendrimers to accommodate more drug molecules with greater strength without inducing too much expansion. This work indicates that tuning the functionalized terminal groups of dendrimers is critical to design efficient dendrimer-based drug delivery systems.

Novel synthesis of N-doped graphene as an efficient electrocatalyst towards oxygen reduction

Nitrogen-doped graphene （NG） was successfully synthesized by a novel, facile, and scalable bottom-up method. The annealed NG （NG-A） possessed high specific surface area and a hierarchical porous texture, and exhibited remarkably improved electrocatalytic activity in the oxygen reduction reaction in both alkaline and acidic media. Ab initio molecular dynamic simulations indicated that rapid H transfer and the thermodynamic stability of six-membered N structures promoted the transformation of N-containing species from pyrrolic to pyridinic at 600 ℃ In O2-staturated 0.1 M KOH solution, the half-wave potential （El/2） of NG-A was only 62 mV lower than that of a commercial Pt/C catalyst, and the limiting current density of NG-A was 0.5 mA.cm-2 larger than that of Pt/C. Koutecky-Levich （K-L） plots and rotating ring-disk electrode measurement indicated a four-electron- transfer pathway in NG-A, which could be ascribed to its high content of pyridinic N.