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1.
Phys Chem Chem Phys ; 24(13): 7901-7908, 2022 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-35311839

RESUMO

The binding of antifreeze proteins (AFPs) to ice needs to be mediated by interfacial water molecules. Our previous study of the effect of AFPs on the dynamics of the interfacial water of freezing at its initial stage has shown that AFPs can promote the growth of ice before binding to it. However, whether different AFPs can promote the freezing of water molecules on the basal and the prismatic surfaces of ice still needs further study. In the present contribution, five representative natural AFPs with different structures and different activities that can be adsorbed on the basal and/or prismatic surfaces of ice are investigated at the atomic level. Our results show that the phenomenon of promoting the growth of ice crystals is not universal. Only hyperactive AFPs (hypAFPs) can promote the growth of the basal plane of ice, while moderately active AFPs cannot. Moreover, this significant promotion is not observed on the prismatic plane regardless of their activity. Further analysis indicates that this promotion may result from the thicker ice/water interface of the basal plane, and the synergy of hypAFPs with ice crystals.


Assuntos
Proteínas Anticongelantes , Gelo , Proteínas Anticongelantes/química , Cristalização , Congelamento , Água
2.
Appl Spectrosc ; : 37028221079395, 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35255722

RESUMO

Analysis of the confined water in hydrogels is essential for understanding the chemical and physical properties. Methods to quantify the content and study the structure of water in hydrogel using near-infrared (NIR) spectroscopy were proposed. The NIR spectra of poly-N,N-dimethylacrylamide (PDMAA) hydrogel with different water contents were measured at different temperatures. A partial least squares (PLS) model was established using the spectra of the samples with water content (wh) from 0.9 to 387.6%. Continuous wavelet transform (CWT) was adopted to calculate the resolution enhanced spectra from which the spectral features of water species with free OH (S0) and with one or two hydrogen bonds (S1 and S2) was obtained. The variation of these water species with water content suggests the existence of the water molecules bonding to NH groups by one hydrogen bond (S1NH) and hydrating the CH groups of the polymer network and bulk-like water. Moreover, the variation of water structures with temperature shows that the release of bulk-like water occurs in the phase transition of the hydrogel, but the S1NH and the hydration water stay unchanged. The former explains the sudden volume shrinkage for the phase transition and the latter may be the reason for the shape memory effect in the repeated swelling and deswelling of hydrogels.

3.
Nat Commun ; 13(1): 1449, 2022 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-35304453

RESUMO

Glucuronoyl esterases (GEs) are α/ß serine hydrolases and a relatively new addition in the toolbox to reduce the recalcitrance of lignocellulose, the biggest obstacle in cost-effective utilization of this important renewable resource. While biochemical and structural characterization of GEs have progressed greatly recently, there have yet been no mechanistic studies shedding light onto the rate-limiting steps relevant for biomass conversion. The bacterial GE OtCE15A possesses a classical yet distinctive catalytic machinery, with easily identifiable catalytic Ser/His completed by two acidic residues (Glu and Asp) rather than one as in the classical triad, and an Arg side chain participating in the oxyanion hole. By QM/MM calculations, we identified deacylation as the decisive step in catalysis, and quantified the role of Asp, Glu and Arg, showing the latter to be particularly important. The results agree well with experimental and structural data. We further calculated the free-energy barrier of post-catalysis dissociation from a complex natural substrate, suggesting that in industrial settings non-catalytic processes may constitute the rate-limiting step, and pointing to future directions for enzyme engineering in biomass utilization.


Assuntos
Esterases , Hidrolases , Biomassa , Catálise , Esterases/metabolismo
4.
Nat Protoc ; 17(4): 1114-1141, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35277695

RESUMO

Designing a reliable computational methodology to calculate protein:ligand standard binding free energies is extremely challenging. The large change in configurational enthalpy and entropy that accompanies the association of ligand and protein is notoriously difficult to capture in naive brute-force simulations. Addressing this issue, the present protocol rests upon a rigorous statistical mechanical framework for the determination of protein:ligand binding affinities together with the comprehensive Binding Free-Energy Estimator 2 (BFEE2) application software. With the knowledge of the bound state, available from experiments or docking, application of the BFEE2 protocol with a reliable force field supplies in a matter of days standard binding free energies within chemical accuracy, for a broad range of protein:ligand complexes. Limiting undesirable human intervention, BFEE2 assists the end user in preparing all the necessary input files and performing the post-treatment of the simulations towards the final estimate of the binding affinity.


Assuntos
Simulação de Dinâmica Molecular , Proteínas , Entropia , Humanos , Ligantes , Ligação Proteica , Proteínas/química , Termodinâmica
5.
J Chem Theory Comput ; 18(3): 1406-1422, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35138832

RESUMO

The string method with swarms of trajectories (SMwST) is an algorithm that identifies a physically meaningful transition pathway─a one-dimensional curve, embedded within a high-dimensional space of selected collective variables. The SMwST algorithm leans on a series of short, unbiased molecular dynamics simulations spawned at different locations of the discretized path, from whence an average dynamic drift is determined to evolve the string toward an optimal pathway. However conceptually simple in both its theoretical formulation and practical implementation, the SMwST algorithm is computationally intensive and requires a careful choice of parameters for optimal cost-effectiveness in applications to challenging problems in chemistry and biology. In this contribution, the SMwST algorithm is presented in a self-contained manner, discussing with a critical eye its theoretical underpinnings, applicability, inherent limitations, and use in the context of path-following free-energy calculations and their possible extension to kinetics modeling. Through multiple simulations of a prototypical polypeptide, combining the search of the transition pathway and the computation of the potential of mean force along it, several practical aspects of the methodology are examined with the objective of optimizing the computational effort, yet without sacrificing accuracy. In light of the results reported here, we propose some general guidelines aimed at improving the efficiency and reliability of the computed pathways and free-energy profiles underlying the conformational transitions at hand.

6.
J Phys Chem B ; 126(7): 1520-1528, 2022 02 24.
Artigo em Inglês | MEDLINE | ID: mdl-35142530

RESUMO

We have investigated, at the atomic level, the ion-fishing mechanism underlying the ion transport across membranes mediated by an artificial ion transporter composed of a hydroxyl-rich cholesterol group, a flexible alkyl chain, and a crown ether. Our results show that the transporter can spontaneously insert into the membrane and switch between the folded (U-shaped) and extended (I-shaped) conformations. The free-energy profile associated with the conformational transition indicates that compared with the U-shaped conformation of the transporter, the I-shaped one is thermodynamically more favorable. Furthermore, the free-energy profiles describing the ion translocation reveal that the transporter capturing the ion in U-shape on one side of the membrane and releasing it in I-shape on the other side constitutes a key way for the highly efficient transport of K+ ions. We present herewith a rigorous and rational framework to decipher the detailed ion-fishing mechanism of transmembrane ion transport with exceptionally high activity.


Assuntos
Bicamadas Lipídicas , Proteínas de Membrana Transportadoras , Transporte de Íons , Íons , Conformação Molecular
7.
Molecules ; 27(2)2022 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-35056768

RESUMO

Temperature-dependent near-infrared (NIR) spectroscopy has been developed and taken as a powerful technique for analyzing the structure of water and the interactions in aqueous systems. Due to the overlapping of the peaks in NIR spectra, it is difficult to obtain the spectral features showing the structures and interactions. Chemometrics, therefore, is adopted to improve the spectral resolution and extract spectral information from the temperature-dependent NIR spectra for structural and quantitative analysis. In this review, works on chemometric studies for analyzing temperature-dependent NIR spectra were summarized. The temperature-induced spectral features of water structures can be extracted from the spectra with the help of chemometrics. Using the spectral variation of water with the temperature, the structural changes of small molecules, proteins, thermo-responsive polymers, and their interactions with water in aqueous solutions can be demonstrated. Furthermore, quantitative models between the spectra and the temperature or concentration can be established using the spectral variations of water and applied to determine the compositions in aqueous mixtures.

8.
Spectrochim Acta A Mol Biomol Spectrosc ; 267(Pt 2): 120581, 2022 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-34776375

RESUMO

To understand the stability of protein in confined environment, the near-infrared (NIR) spectra of aqueous solutions and reverse micelles (RMs) containing bovine serum albumin (BSA), human serum albumin (HSA) and ovalbumin (OVA) were measured at different temperature. With the resolution enhanced spectra calculated by continuous wavelet transform (CWT), the intensity change of the α-helix band at 4617 cm-1 with temperature shows a clear denaturation of the protein in aqueous solution but not in RMs. The effect of the confined environment on the stability of the proteins is indicated. More importantly, the intensity change of the spectral bands of water around 6956 and 6842 cm-1 provide an evidence for the denaturation, suggesting that water can be a probe exhibiting the structural change of proteins. Furthermore, comparing the spectral features of different water structures obtained by principal component analysis (PCA) from the spectra of RM with and without BSA, it is demonstrated that the bridging water connecting NH in protein and SO in the inner surface of RM may be the reason for the stabilization.


Assuntos
Espectroscopia de Luz Próxima ao Infravermelho , Água , Humanos , Análise de Componente Principal , Soroalbumina Bovina , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura
9.
J Chem Inf Model ; 62(1): 1-8, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-34939790

RESUMO

Importance-sampling algorithms leaning on the definition of a model reaction coordinate (RC) are widely employed to probe processes relevant to chemistry and biology alike, spanning time scales not amenable to common, brute-force molecular dynamics (MD) simulations. In practice, the model RC often consists of a handful of collective variables (CVs) chosen on the basis of chemical intuition. However, constructing manually a low-dimensional RC model to describe an intricate geometrical transformation for the purpose of free-energy calculations and analyses remains a daunting challenge due to the inherent complexity of the conformational transitions at play. To solve this issue, remarkable progress has been made in employing machine-learning techniques, such as autoencoders, to extract the low-dimensional RC model from a large set of CVs. Implementation of the differentiable, nonlinear machine-learned CVs in common MD engines to perform free-energy calculations is, however, particularly cumbersome. To address this issue, we present here a user-friendly tool (called MLCV) that facilitates the use of machine-learned CVs in importance-sampling simulations through the popular Colvars module. Our approach is critically probed with three case examples consisting of small peptides, showcasing that through hard-coded neural network in Colvars, deep-learning and enhanced-sampling can be effectively bridged with MD simulations. The MLCV code is versatile, applicable to all the CVs available in Colvars, and can be connected to any kind of dense neural networks. We believe that MLCV provides an effective, powerful, and user-friendly platform accessible to experts and nonexperts alike for machine-learning (ML)-guided CV discovery and enhanced-sampling simulations to unveil the molecular mechanisms underlying complex biochemical processes.


Assuntos
Aprendizado de Máquina , Simulação de Dinâmica Molecular , Algoritmos , Entropia , Redes Neurais de Computação
10.
Phys Chem Chem Phys ; 24(3): 1286-1299, 2022 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-34951435

RESUMO

With their development in the past decade, molecular machines, which achieve specific tasks by responding to external stimuli, have gradually come to be regarded as powerful tools for a wide range of applications, rather than interesting molecular toys. This conceptual change in turn motivates scientists to design molecular machines with complex architectures. Due to the lack of general principles bridging the functions and the chemical structures of molecular machines, experience-based design becomes difficult with the increase of size and complexity of the architectures. Computer-aided molecular-machine design, therefore, has attracted widespread attention on account of its ability to model and investigate complex molecular architectures without too much time and expense required for synthetic experiments. Using leading-edge numerical-simulation techniques, the mechanisms underlying achieving tasks through response to external stimuli of a large number of existing molecular machines have been successfully explored. Based on the experience of studying existing molecular machines, generalized methodologies of predicting the properties and working principles of molecular candidates have been established, paving the way for de novo computer-aided design of molecular machines. In this perspective, we introduce cutting-edge techniques that have been applied for investigating and designing molecular machines. We show paradigms of computer-aided design of molecular machines, which can serve as guidelines for the investigation of new supramolecular architectures. Moreover, we discuss the limitations and possible future developments of current techniques and methodologies in the field of computer-aided design of molecular machines.

11.
Spectrochim Acta A Mol Biomol Spectrosc ; 266: 120417, 2022 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-34600324

RESUMO

Taking formamide (FA) as a model compound of protein, the water structure in the ternary mixtures of dimethyl sulfoxide (DMSO)-water-FA was studied by near-infrared (NIR) spectroscopy. The interaction of DMSO and water, and the effect of FA on the interaction, were analyzed with the help of chemometric methods. Continuous wavelet transform (CWT) was used to enhance the resolution of the spectra. A peak at 6437 cm-1 depicting the interaction of DMSO and water through hydrogen bonding (SO…HO) was observed in the transformed spectra. When FA exists in the mixture, the intensity of the peak decreases with the increase of formamide content, showing that FA may replace the water to form the hydrogen bond of SO and HN. In addition, temperature-dependent NIR spectroscopy was used to analyze the effect of the three components on the spectral variation with temperature. Analyzing the spectral data by alternating trilinear decomposition (ATLD) and multiple linear regression, two varying spectral features were obtained that are related to water and DMSO, but no spectral feature was found that significantly varies with the content of FA. The result implies that DMSO is still the key component to prevent the water from icing, although FA may reduce slightly the anti-freezing effect.


Assuntos
Espectroscopia de Luz Próxima ao Infravermelho , Água , Dimetil Sulfóxido , Ligação de Hidrogênio , Proteínas
12.
Phys Chem Chem Phys ; 23(45): 25706-25711, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34755729

RESUMO

Hyaluronan (HA) is a major component in the extracellular matrix and is responsible for maintaining the water content of the skin. However, the function and moisturizing mechanism at the atomic level of HA remain only partially understood. Investigating the interactions of HA and other skin components can help us understand how the former moisturizes the skin. Considering that aquaporin-3 (AQP3) is a protein responsible for transmembrane water transport in the human skin, we have, therefore, investigated the interactions of AQP3 and HA with different molecular weights using molecular dynamics simulations in the present work. Our results indicate that HA can adsorb onto AQP3 and decrease water mobility around the latter. In addition, the permeation rate of water through AQP3 can also be decreased by HA, and this phenomenon is particularly obvious for small molecular HA. Moreover, we found that large molecular HA can link two adjacent membranes in the extracellular matrix, increasing the adhesion between the membranes in the periplasm. The results of the present study indicate that HA is a natural regulator of AQP3, revealing the synergetic function of HA and AQP3 in the extracellular matrix of the skin.


Assuntos
Aquaporina 3/metabolismo , Ácido Hialurônico/metabolismo , Aquaporina 3/química , Humanos , Ácido Hialurônico/química , Permeabilidade , Água/química , Água/metabolismo
13.
J Chem Inf Model ; 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34711054

RESUMO

The antifreeze mechanism of antifreeze proteins (AFPs) evolved by organisms has been widely studied. However, detailed knowledge of the synergy between AFPs and ice crystals still remains fragmentary. In the present contribution, the cooperative effect of the hyperactive insect antifreeze protein TmAFP and ice crystals on the interfacial water during the entire process of inhibiting ice growth is systematically investigated at the atomic level and compared with its low activity mutant and a nonantifreeze protein. The results indicate a significant synergy between TmAFP and ice crystals, which enables the TmAFP to promote the ice growth before adsorbing on the surfaces of the ice crystals, while the mutant and the nonantifreeze protein cannot promote the ice growth due to the lack of this synergy. When TmAFP approaches the ice surface, the interfacial water is induced by both the AFP and the ice crystals to form the anchored clathrate motif, which binds TmAFP to the ice surface, resulting in a local increase in the curvature of the ice surface, thereby inhibiting the growth of ice. In this study, three stages, namely, promotion, adsorption, and inhibition, are observed in the complete process of TmAFP inhibiting ice growth, and the synergistic mechanism between protein and ice crystals is revealed. The results are helpful for the design of antifreeze proteins and bioinspired antifreeze materials with superior performance.

14.
J Chem Theory Comput ; 17(7): 3886-3894, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34106706

RESUMO

Amid collective-variable (CV)-based importance-sampling algorithms, a hybrid of the extended adaptive biasing force and the well-tempered metadynamics algorithms (WTM-eABF) has proven particularly cost-effective for exploring the rugged free-energy landscapes that underlie biological processes. However, as an inherently CV-based algorithm, this hybrid scheme does not explicitly accelerate sampling in the space orthogonal to the chosen CVs, thereby limiting its efficiency and accuracy, most notably in those cases where the slow degrees of freedom of the process at hand are not accounted for in the model transition coordinate. Here, inspired by Gaussian-accelerated molecular dynamics (GaMD), we introduce the same CV-independent harmonic boost potential into WTM-eABF, yielding a hybrid algorithm coined GaWTM-eABF. This algorithm leans on WTM-eABF to explore the transition coordinate with a GaMD-mollified potential and recovers the unbiased free-energy landscape through thermodynamic integration followed by proper reweighting. As illustrated in our numerical tests, GaWTM-eABF effectively overcomes the free-energy barriers in orthogonal space and correctly recovers the unbiased potential of mean force (PMF). Furthermore, applying both GaWTM-eABF and WTM-eABF to two biologically relevant processes, namely, the reversible folding of (i) deca-alanine and (ii) chignolin, our results indicate that GaWTM-eABF reduces the uncertainty in the PMF calculation and converges appreciably faster than WTM-eABF. Obviating the need of multiple-copy strategies, GaWTM-eABF is a robust, computationally efficient algorithm to surmount the free-energy barriers in orthogonal space and maps with utmost fidelity the free-energy landscape along selections of CVs. Moreover, our strategy that combines WTM-eABF with GaMD can be easily extended to other biasing-force algorithms.

15.
J Chem Theory Comput ; 17(7): 3908-3915, 2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34125530

RESUMO

Modifying pair-specific Lennard-Jones parameters through the nonbonded FIX (NBFIX) feature of the CHARMM36 force field has proven cost-effective for improving the description of cation-π interactions in biological objects by means of pairwise additive potential energy functions. Here, two sets of newly optimized CHARMM36 force-field parameters including NBFIX corrections, coined CHARMM36m-NBF and CHARMM36-WYF, and the original force fields, namely CHARMM36m and Amber ff14SB, are used to determine the standard binding free energies of seven protein-ligand complexes containing cation-π interactions. Compared with precise experimental measurements, our results indicate that the uncorrected, original force fields significantly underestimate the binding free energies, with a mean error of 5.3 kcal/mol, while the mean errors of CHARMM36m-NBF and CHARMM36-WYF amount to 0.8 and 2.1 kcal/mol, respectively. The present study cogently demonstrates that the use of modified parameters jointly with NBFIX corrections dramatically increases the accuracy of the standard binding free energy of protein-ligand complexes dominated by cation-π interactions, most notably with CHARMM36m-NBF.


Assuntos
Proteínas/química , Cátions , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Teoria Quântica , Termodinâmica
16.
J Chem Inf Model ; 61(5): 2116-2123, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-33906354

RESUMO

Accurate absolute binding free-energy estimation in silico, following either an alchemical or a geometrical route, involves several subprocesses and requires the introduction of geometric restraints. Human intervention, for instance, to define the necessary collective variables, prepare the input files, monitor the simulation, and perform post-treatments is, however, tedious, cumbersome, and prone to errors. With the aim of automating and streamlining free-energy calculations, especially for nonexperts, version 2.0 of the binding free energy estimator (BFEE2) provides both standardized alchemical and geometrical workflows and obviates the need for extensive human intervention to guarantee complete reproducibility of the results. To achieve the largest gamut of protein-ligand and, more generally, of host-guest complexes, BFEE2 supports most academic force fields, such as CHARMM, Amber, OPLS, and GROMOS. Configurational files are generated in the NAMD and Gromacs formats, and all the post-treatments are performed in an automated fashion. Moreover, convergence of the free-energy calculation can be monitored from the intermediate files generated during the simulation. All in all, BFEE2 is a foolproof, versatile tool for accurate absolute binding free-energy calculations, assisting the end-user over a broad range of applications.


Assuntos
Simulação de Dinâmica Molecular , Entropia , Humanos , Ligantes , Reprodutibilidade dos Testes , Termodinâmica
17.
J Phys Chem Lett ; 12(13): 3281-3287, 2021 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-33764777

RESUMO

Assisting ion transport across membranes by means of sophisticated molecular machines has promising applications in the treatment of diseases induced by dysregulated ion transport. To develop such nanoscale devices imbued with specific functions, rational de novo design, upstream from costly syntheses, is eminently desirable but would require the atomic detail of the translocation mechanism, which is still largely missing. We have explored the full ion capture-transport-release process over an aggregate simulation time of 60 µs, employing leading-edge enhanced-sampling algorithms to disentangle with unprecedented detail the mechanism that underlies ion transport mediated by a membrane-spanning [2]rotaxane composed of an ion carrier linked to a wheel threaded onto an axle. Beyond validating the reliability of our methodology through careful examination of the clockwork of a documented nanomachine, we put forth an original pH-controlled nano-object that can assist transient unidirectional ion transport across membranes.


Assuntos
Membranas Artificiais , Nanotecnologia/métodos , Concentração de Íons de Hidrogênio , Transporte de Íons , Simulação de Dinâmica Molecular , Nanotecnologia/instrumentação , Rotaxanos/química , Termodinâmica
18.
Spectrochim Acta A Mol Biomol Spectrosc ; 253: 119573, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33618264

RESUMO

Regulating the folding state by denaturants is essential for the structure and function of proteins. Poly(N-isopropyl acrylamide) (PNIPAM) is usually regarded as a model for protein denaturation. The effects of urea, as a denaturant, on the aggregations of PNIPAM was studied by temperature-dependent near-infrared (NIR) spectroscopy, and particularly the variation of water structures was analyzed. The NIR spectra of the polymer-urea solutions containing different polymer concentrations were measured at different temperatures. N-way principal component analysis (NPCA) was performed to observe the spectral information. Three principal components (PCs) containing the spectral information of CH groups were obtained, showing three kinds of CH in the system. Obvious dehydration of the three CH groups occurs at 27.5 °C in solution, but the temperature turns to 27 °C for two kinds of the CH and 26.5 °C for the third one, respectively, in the urea-add solution. The effect of urea on the formation of the intramolecular hydrogen bonds that promotes polymer folding is suggested. The spectral information of NH in urea molecule indicates that the direct interaction of urea and polymer facilitates the stability of the polymer globule state. Furthermore, the spectral information of OH shows that the release of the water molecules with three hydrogen bonds (S3), which may connect the NH and CO groups in PNIPAM in solution, leads to the phase transition. When urea is added, urea may reduce the content of the S3 water to facilitate the release, making the phase transition at a low temperature.

19.
J Phys Chem Lett ; 12(1): 613-619, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33382629

RESUMO

To understand how different external stimuli affect the cooperative motions in a molecular machine consisting of multiple components, we have investigated at the atomic level the effects of pH, solvent, and ionic strength on the mechanism underlying the ring-through-ring movement in a saturated [3]rotaxane. Our results indicate that different external stimuli regulate the stable states, the shuttling rate, and the mechanism that governs the ring-through-ring motion by controlling the cooperative movement of the components and triggering a gamut of responses, thereby opening to a vast number of potential applications, such as quaternary logical calculations. The present work cogently demonstrates that with existing nanomachines possessing a simple topology, but using different external stimuli-an approach coined multidimensional regulation-challenging tasks requiring precise control of the molecular motions at play can be achieved, and our methodology is particularly germane for de novo design of intelligent molecular machines.

20.
J Chem Theory Comput ; 16(10): 6397-6407, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-32852943

RESUMO

Cation-π interactions play a significant role in a host of processes eminently relevant to biology. However, polarization effects arising from the interaction of cations with aromatic moieties have long been recognized to be inadequately described by pairwise additive force fields. In the present work, we address this longstanding shortcoming through the nonbonded FIX (NBFIX) feature of the CHARMM36 force field, modifying pair-specific Lennard-Jones (LJ) parameters, while circumventing the limitations of the Lorentz-Berthelot combination rules. The potentials of mean force (PMFs) characterizing prototypical cation-π interactions in aqueous solutions are first determined using a hybrid quantum mechanical/molecular mechanics (QM/MM) strategy in conjunction with an importance-sampling algorithm. The LJ parameters describing the cation-π pairs are then optimized to match the QM/MM PMFs. The standard binding free energies of nine cation-π complexes, i.e., toluene, para-cresol, and 3-methyl-indole interacting with either ammonium, guanidinium, or tetramethylammonium, determined with this new set of parameters agree well with the experimental measurements. Additional simulations were carried out on three different classes of biological objects featuring cation-π interactions, including five individual proteins, three protein-ligand complexes, and two protein-protein complexes. Our results indicate that the description of cation-π interactions is overall improved using NBFIX corrections, compared with the standard pairwise additive force field. Moreover, an accurate binding free energy calculation for a protein-ligand complex containing cation-π interactions (2BOK) shows that using the new parameters, the experimental binding affinity can be reproduced quantitatively. Put together, the present work suggests that the NBFIX parameters optimized here can be broadly utilized in the simulation of proteins in an aqueous solution to enhance the representation of cation-π interactions, at no additional computational cost.


Assuntos
Simulação de Dinâmica Molecular , Proteínas/química , Teoria Quântica , Cátions/química , Ligantes , Termodinâmica
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