Amino Acid Side Chain Analogues Research Articles

Quantifying Induced Dipole Effects in Small Molecule Permeation in a Model Phospholipid Bilayer.

The cell membrane functions as a semipermeable barrier that governs the transport of materials into and out of cells. The bilayer features a distinct dielectric gradient due to the amphiphilic nature of its lipid components. This gradient influences various aspects of small molecule permeation and the folding and functioning of membrane proteins. Here, we employ polarizable molecular dynamics simulations to elucidate the impact of the electronic environment on the permeation process. We simulated eight distinct amino-acid side chain analogs within a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine bilayer using the Drude polarizable force field (FF). Our approach includes both unbiased and umbrella sampling simulations. By using a polarizable FF, we sought to investigate explicit dipole responses in relation to local electric fields along the membrane normal. We evaluate molecular dipole moments, which exhibit variation based on their localization within the membrane, and compare the outcomes with analogous simulations using the nonpolarizable CHARMM36 FF. This comparative analysis aims to discern characteristic differences in the free energy surfaces of permeation for the various amino-acid analogs. Our results provide the first systematic quantification of the impact of employing an explicitly polarizable FF in this context compared to the fixed-charge convention inherent to nonpolarizable FFs, which may not fully capture the influence of the membrane dielectric gradient.

Molecular Dynamics Study of the Antifouling Mechanism of Hydrophilic Polymer Brushes.

We perform all-atom molecular dynamics simulations of the adsorption of amino acid side-chain analogues on polymer brushes. The analogues examined are nonpolar isobutane, polar propionamide, negatively charged propionate ion, and positively charged butylammonium ion. The polymer brushes consist of a sheet of graphene and strongly hydrophilic poly(carboxybetaine methacrylate) (PCBMA) or weakly hydrophilic poly(2-hydroxyethyl methacrylate) (PHEMA). The effective interactions between isobutane and polymer chains are repulsive for PCBMA and attractive for PHEMA. Gibbs energy decomposition analysis shows that this is due to the abundance of water in the PCBMA brush, which increases the steric repulsion and decreases the Lennard-Jones attraction. The affinity of the hydrophilic analogues is low for both PCBMA and PHEMA chains, but the balance between the components of the Gibbs energy is different for the two polymers. The simulations are performed at several θ, where θ is the degree of overlap of polymer chains. The antifouling performance against the neutral analogues is better for PCBMA than for PHEMA in the low and high θ regimes. However, in the middle θ regime, the antifouling performance of PHEMA is close to or better than that of PCBMA. This is attributed to the formation of a dense layer of PHEMA on the graphene surface that inhibits direct adsorption of analogue molecules on graphene. The charged analogues do not bind to either the PHEMA or PCBMA brush irrespective of θ.

Biomolecular Adsorprion at ZnS Nanomaterials: A Molecular Dynamics Simulation Study of the Adsorption Preferences, Effects of the Surface Curvature and Coating.

The understanding of interactions between nanomaterials and biological molecules is of primary importance for biomedical applications of nanomaterials, as well as for the evaluation of their possible toxic effects. Here, we carried out extensive molecular dynamics simulations of the adsorption properties of about 30 small molecules representing biomolecular fragments at ZnS surfaces in aqueous media. We computed adsorption free energies and potentials of mean force of amino acid side chain analogs, lipids, and sugar fragments to ZnS (110) crystal surface and to a spherical ZnS nanoparticle. Furthermore, we investigated the effect of poly-methylmethacrylate (PMMA) coating on the adsorption preferences of biomolecules to ZnS. We found that only a few anionic molecules: aspartic and glutamic acids side chains, as well as the anionic form of cysteine show significant binding to pristine ZnS surface, while other molecules show weak or no binding. Spherical ZnS nanoparticles show stronger binding of these molecules due to binding at the edges between different surface facets. Coating of ZnS by PMMA changes binding preferences drastically: the molecules that adsorb to a pristine ZnS surface do not adsorb on PMMA-coated surfaces, while some others, particularly hydrophobic or aromatic amino-acids, show high binding affinity due to binding to the coating. We investigate further the hydration properties of the ZnS surface and relate them to the binding preferences of biomolecules.

Partitioning free energies and induced dipole response of small molecules across a POPC membrane using polarizable molecular dynamics.

The cell membrane is the semi-permeable barrier that regulates flux of materials in and out of the cell. The membrane has a characteristic dielectric gradient due to the amphiphilic nature of its constituent lipids, which have polar head groups and hydrophobic tails. This gradient plays governs many aspects of small-molecule partitioning and membrane protein folding and function. Atomistic details of small-molecule partitioning related to hydration and electronic polarization are still largely unknown. Here, we used polarizable molecular dynamics simulations to understand how the electronic environment influences the process of partitioning. We performed a series of unbiased and umbrella sampling (US) simulations using the Drude polarizable force field (FF) for six different amino-acid sidechain analogs in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer. Using a polarizable FF such as Drude allows for the investigation of explicit dipole responses as a function of local electric fields along the membrane normal. We assessed molecular dipole moments, which vary as a function of localization within the membrane, and compared outcomes of the Drude FF simulations to those of the nonpolarizable CHARMM36 FF to investigate the differences in the free energy surfaces of partitioning for our different amino-acid analogs. In doing so, we sought to quantify the effects of using the fixed-charge convention of nonpolarizable FFs, which may average out the influence of the membrane dielectric gradient. We show how polarity of small molecules influences their partitioning and describe key differences in the free energy surfaces between polarizable and nonpolarizable systems in these contexts. This work serves as a foundation for future investigations into polarizable simulations of drug partitioning, as well as simulations of membrane proteins.

Polarization in partitioning: quantifying the effects of induced dipoles on amino acid sidechain analogs in a POPC membrane

The cell membrane is a semi-permeable barrier that regulates the exchange of materials between the cell and its surroundings. Arising from the amphiphilic nature of individual lipids, the bilayer has a characteristic dielectric gradient from the polar headgroups and water interface to the nonpolar tails deep in the membrane interior. This gradient is crucial in different biological processes, such as small molecule partitioning and membrane protein folding and function. While much is known about the composition and function of membranes, the atomistic details of small molecule partitioning and protein folding are not fully understood.

Molecular dynamics study of the interactions between a hydrophilic polymer brush on graphene and amino acid side chain analogues in water.

We perform all-atom molecular dynamics simulations of poly(2-hydroxyethyl methacrylate) (PHEMA) brushes in aqueous solutions of isobutane, propionamide, and sodium propionate. These solutes are side chain analogues to leucine, glutamine, and glutamic acid, respectively. We compute the Gibbs energy profile of the solute's adsorption to the polymer brush and decompose it into the contributions from the steric repulsion, van der Waals interaction, and Coulomb interaction to reveal the energetic origin of repulsion or attraction of the solute by the polymer brush. The Henry adsorption constant is the amount of adsorption normalized by the concentration in aqueous solution. We examine the dependence of this quantity on the grafting density and chain length. Our results suggest that the concurrent primary and ternary adsorption mechanism may be more important than previously expected when the solute is hydrophobic.

Interaction of divalent cations and amino acids in bulk water: Molecular simulations with neural network potentials

Understanding the interaction mechanism between divalent metal ions with amino acids is of great significance to understand the interaction between metal ions with proteins. In this study, the interaction mechanisms of Mg2+, Ca2+, and Zn2+ with amino acid side chain analogs in water were systematically studied by combining neural network potential energy surface, molecular dynamics simulation and umbrella sampling. The calculated potential mean forces not only reveal the binding process of each ion and amino acid, the most stable coordination structure, but also show the difference between different ions. In addition, we also use the neural network based potential of mean force as a standard to benchmark classical force fields, which is also meaningful for the development of force fields targeting metal ions.

Adsorption characteristics of peptides on ω-functionalized self-assembled monolayers: a molecular dynamics study.

Molecular dynamics simulations were employed to investigate the adsorption behavior of a variety of amino-acid side-chain analogs (SCAs) and a β-hairpin (HP7) peptide on a series of liquid-like self-assembled monolayers (SAMs) with terminal functional groups of -OH, -OCH3, -CH3, and -CF3. The relationships between the adsorption free energy of the SCAs and the interfacial properties of water on the SAMs were examined to determine the acute predictors of protein adsorption on the SAM surfaces. The structural changes of HP7 on the SAM surfaces were also investigated to understand the relationship between the surface nature and protein denaturation. It was found that the adsorption free energy of the SCAs was linearly related to the surface hydrophobicity, which was computed as the free energy of cavity formation near the SAM-water interfaces. In addition, the hydrophobic -CH3 and -CF3 SAMs produced substantial conformational changes in HP7 because of the strong hydrophobic attractions to the nonpolar side chains. The hydrophilic surface terminated by -OH also promoted structural changes in HP7 resulting from the formation of hydrogen bonds between the hydrophilic tail and HP7. Consequently, the moderate amphiphilic surface terminated by -OCH3 avoided the denaturation of HP7 most efficiently, thus improving the biocompatibility of the surface. In conclusion, these results provide a deep understanding of protein adsorption for a wide range of polymeric surfaces, and they can potentially aid the design of appropriate biocompatible coatings for medical applications.

Force Field Benchmark of Amino Acids. 3. Hydration with Scaled Lennard-Jones Interactions.

Classical protein force fields were reported with too weak protein-water interactions relative to protein-protein interactions, leading to more compact structures and artificial protein aggregation. Here we investigated the impacts of scaled Lennard-Jones (LJ) interactions on the hydration of amino acids and the simulation of folded and intrinsically disordered proteins (IDPs). The obtained optimal scaling parameters reproduce accurately hydration free energies of neutral amino acid side chain analogues and do not affect the compactness and structural stability of folded proteins significantly. The scaling leads to less compact IDPs and varies from case to case. Strengthening the interactions between protein and water oxygen or hydrogen atoms by increasing the interacting LJ well depth (ε) appears more effective than weakening protein-protein interactions by reducing the interacting dispersion coefficients (C6). We demonstrate that weakening water-water interactions is a solution as well to obtaining more favorable protein-water interactions in an indirect way, although modern force fields like Amber ff19SB and a99SB-disp tend to use water models with strong water-water interactions. This is likely a compromise between strong protein-protein interactions and strong water-water interactions. Independent optimization of protein force fields and water models is therefore needed to make both interactions more close to reality, leading to good accuracy without bias or scaling.

Capturing Choline-Aromatics Cation-π Interactions in the MARTINI Force Field.

Cation−π interactions play an important role in biomolecular recognition, including interactions between membrane phosphatidylcholine lipids and aromatic amino acids of peripheral proteins. While molecular mechanics coarse grain (CG) force fields are particularly well suited to simulate membrane proteins in general, they are not parameterized to explicitly reproduce cation−π interactions. We here propose a modification of the polarizable MARTINI coarse grain (CG) model enabling it to model membrane binding events of peripheral proteins whose aromatic amino acid interactions with choline headgroups are crucial for their membrane binding. For this purpose, we first collected and curated a dataset of eight peripheral proteins from different families. We find that the MARTINI CG model expectedly underestimates aromatics–choline interactions and is unable to reproduce membrane binding of the peripheral proteins in our dataset. Adjustments of the relevant interactions in the polarizable MARTINI force field yield significant improvements in the observed binding events. The orientation of each membrane-bound protein is comparable to reference data from all-atom simulations and experimental binding data. We also use negative controls to ensure that choline–aromatics interactions are not overestimated. We finally check that membrane properties, transmembrane proteins, and membrane translocation potential of mean force (PMF) of aromatic amino acid side-chain analogues are not affected by the new parameter set. This new version “MARTINI 2.3P” is a significant improvement over its predecessors and is suitable for modeling membrane proteins including peripheral membrane binding of peptides and proteins.

Correction terms for the solvation free energy functional of three-dimensional reference interaction site model based on the reference-modified density functional theory

Recently, we derived the reference-modified density functional theory (RMDFT) to calculate the solvation free energy (SFE) with high accuracy, introducing a reference system to the DFT for polyatomic molecular liquids. The RMDFT functional consists of the DFT using second-order approximation (DFT(D)) functional and the correction terms. The DFT(D) functional are equivalent to the Singer-Chandler formula for the hypernetted chain closure equation. The contribution of the correction terms has a strong correlation with the partial molar volume (PMV) of solute. Thus, the RMDFT functional has almost the same accuracy as the PMV correction. Furthermore, we combined the Singer-Chandler formula for the Kovalenko-Hirata closure and the correction terms to avoid inconsistency between the closure equation and the SFE functional. It become clear that the inconsistency is unimportant, whereas the combined functional works well for the amino acid side chain analogues molecules.

Correction to Direct Comparison of Amino Acid and Salt Interactions with Double-Stranded and Single-Stranded DNA from Explicit-Solvent Molecular Dynamics Simulations.

Given the ubiquitous nature of protein–DNA interactions, it is important to understand the interaction thermodynamics of individual amino acid side chains for DNA. One way to assess these preferences is to perform molecular dynamics (MD) simulations. Here we report MD simulations of 20 amino acid side chain analogs interacting simultaneously with both a 70-base-pair double-stranded DNA and with a 70-nucleotide single-stranded DNA. The relative preferences of the amino acid side chains for dsDNA and ssDNA match well with values deduced from crystallographic analyses of protein–DNA complexes. The estimated apparent free energies of interaction for ssDNA, on the other hand, correlate well with previous simulation values reported for interactions with isolated nucleobases, and with experimental values reported for interactions with guanosine. Comparisons of the interactions with dsDNA and ssDNA indicate that, with the exception of the positively charged side chains, all types of amino acid side chain interact...

The Impact of Using Single Atomistic Long-Range Cutoff Schemes with the GROMOS 54A7 Force Field.

With the recent increase in computing power, the molecular modeling community is now more focused on improving the accuracy and overall quality of biomolecular simulations. For the available simulation packages, force fields, and all other associated methods used, this relates to how well they describe the conformational space and thermodynamic properties of a biomolecular system. The parameter sets of GROMOS force fields have been parametrized and validated with the reaction field (RF) method using charge groups and a twin-range cutoff scheme (0.8/1.4 nm). However, the most recent versions of GROMACS (since v.2016) discontinued the support for charge groups. To take full advantage of the newer and faster versions of this software package with GROMOS 54A7 and RF, we need to evaluate the impact of using a single cutoff scheme (vs twin-range) and of using the Verlet list update method (which is atomistic) compared to the group-based cutoff scheme. Our results show that the GROMOS 54A7 force field seems consistent with a single cutoff, since the resulting conformation and protonation ensembles were indistinguishable. The GROMOS parametrization procedure was also reproduced using an atomistic cutoff scheme, and we have observed that the hydration free energy values of small amino acid side-chain analogues were similar to the ones obtained with the group-based protocol. We do observe a small impact of the atomistic cutoff scheme in the conformational space of the model systems studied (G1-PAMAM and DMPC). However, since the structural properties of these systems are well converged for the cutoff range used (1.4-2.0 nm), unlike with the group-based cutoff schemes, we are confident that the atomistic cutoff can be adopted with RF for MD and constant-pH MD biomolecular simulations using the GROMOS 54A7 force field.

Force Field Benchmark of Amino Acids. 2. Partition Coefficients between Water and Organic Solvents.

2018 , 58 , 1037 - 1052 ), may aid in the development and systematic improvements of classical force fields to model proteins in aqueous and nonaqueous phases accurately.

Partition coefficients of methylated DNA bases obtained from free energy calculations with molecular electron density derived atomic charges

Partition coefficients serve in various areas as pharmacology and environmental sciences to predict the hydrophobicity of different substances. Recently, they have also been used to address the accuracy of force fields for various organic compounds and specifically the methylated DNA bases. In this study, atomic charges were derived by different partitioning methods (Hirshfeld and Minimal Basis Iterative Stockholder) directly from the electron density obtained by electronic structure calculations in a vacuum, with an implicit solvation model or with explicit solvation taking the dynamics of the solute and the solvent into account. To test the ability of these charges to describe electrostatic interactions in force fields for condensed phases, the original atomic charges of the AMBER99 force field were replaced with the new atomic charges and combined with different solvent models to obtain the hydration and chloroform solvation free energies by molecular dynamics simulations. Chloroform-water partition coefficients derived from the obtained free energies were compared to experimental and previously reported values obtained with the GAFF or the AMBER-99 force field. The results show that good agreement with experimental data is obtained when the polarization of the electron density by the solvent has been taken into account, and when the energy needed to polarize the electron density of the solute has been considered in the transfer free energy. These results were further confirmed by hydration free energies of polar and aromatic amino acid side chain analogs. Comparison of the two partitioning methods, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS), revealed some deficiencies in the Hirshfeld-I method related to the unstable isolated anionic nitrogen pro-atom used in the method. Hydration free energies and partitioning coefficients obtained with atomic charges from the MBIS partitioning method accounting for polarization by the implicit solvation model are in good agreement with the experimental values. © 2018 Wiley Periodicals, Inc.

Force Field Benchmark of Amino Acids: I. Hydration and Diffusion in Different Water Models.

Thermodynamic and kinetic properties are of critical importance for the applicability of computational models to biomolecules such as proteins. Here we present an extensive evaluation of the Amber ff99SB-ILDN force field for modeling of hydration and diffusion of amino acids with three-site (SPC, SPC/E, SPC/Eb, and TIP3P), four-site (TIP4P, TIP4P-Ew, and TIP4P/2005), and five-site (TIP5P and TIP5P-Ew) water models. Hydration free energies (HFEs) of neutral amino acid side chain analogues have little dependence on the water model, with a root-mean-square error (RMSE) of ∼1 kcal/mol from experimental observations. On the basis of the number of interacting sites in the water model, HFEs of charged side chains can be putatively classified into three groups, of which the group of three-site models lies between those of four- and five-site water models; for each group, the water model dependence is greatly eliminated when the solvent Galvani potential is considered. Some discrepancies in the location of the first hydration peak ( RRDF) in the ion-water radial distribution function between experimental and calculated observations were detected, such as a systematic underestimation of the acetate (Asp side chain) ion. The RMSE of calculated diffusion coefficients of amino acids from experiment increases linearly with the increasing diffusion coefficients of the solvent water models at infinite dilution. TIP3P has the fastest diffusivity, in line with literature findings, while the "FB" and "OPC" water model families as well as TIP4P/2005 perform well, within a relative error of 5%, and TIP4P/2005 yields the most accurate estimate for the water diffusion coefficient. All of the tested water models overestimate amino acid diffusion coefficients by approximately 40% (TIP4P/2005) to 200% (TIP3P). Scaling of protein-water interactions with TIP4P/2005 in the Amber ff99SBws and ff03ws force fields leads to more negative HFEs but has little influence on the diffusion of amino acids. The most recent FF/water combinations of ff14SB/OPC3, ff15ipq/SPC/Eb, and fb15/TIP3P-FB do not show obvious improvements in accuracy for the tested quantities. These findings here establish a benchmark that may aid in the development and improvement of classical force fields to accurately model protein dynamics and thermodynamics.

Essence of Small Molecule-Mediated Control of Hydroxyapatite Growth: Free Energy Calculations of Amino Acid Side Chain Analogues

Much effort has been exerted to unravel the bone biomineralization mechanism by which the growth of plate-shaped crystals of hydroxyapatite (HAP) is regulated within a fibrillar collagen matrix. Acidic noncollagenous acidic proteins (NCPs) bearing a large number of carboxylate and phosphorylate amino acid residues are effective regulators of HAP crystal morphology. To reveal the energetic and structural essence of the growth-regulation mechanism, we performed here advanced molecular dynamics simulations to obtain adsorption free energies of side chain analogues (SCAs) of acidic and uncharged polar amino acids as well as the corresponding zwitterionic backbone (BB) fragment and compared the results to those for the entire amino acid molecule. We observed that negatively charged SCAs (phosphoserine in two protonation states, aspartate and glutamate) and the zwitterionic BB preferentially bind to the HAP (100) surface compared to the (001) face, consistent with [100] being the preferred growth direction for ...

Saturation Mutagenesis by Efficient Free-Energy Calculation.

Single-point mutations in proteins can greatly influence protein stability, binding affinity, protein function or its expression per se. Here, we present accurate and efficient predictions of the free energy of mutation of amino acids. We divided the complete mutational free energy into an uncharging step, which we approximate by a third-power fitting (TPF) approach, and an annihilation step, which we approximate using the one-step perturbation (OSP) method. As a diverse set of test systems, we computed the solvation free energy of all amino acid side chain analogues and obtained an excellent agreement with thermodynamic integration (TI) data. Moreover, we calculated mutational free energies in model tripeptides and established an efficient protocol involving a single reference state. Again, the approximate methods agreed excellently with the TI references, with a root-mean-square error of only 3.6 kJ/mol over 17 mutations. Our combined TPF+OSP approach does show not only a very good agreement but also a 2-fold higher efficiency than full blown TI calculations.

A coarse-grained model of the effective interaction for charged amino acid residues and its application to formation of GCN4-pLI tetramer

ABSTRACTWe present a simple coarse-grained model of the effective interaction for charged amino acid residues, such as Glu and Lys, in a water solvent. The free-energy profile as a function of the distance between two charged amino acid side-chain analogues in an explicit water solvent is calculated with all-atom molecular dynamics simulation and thermodynamic integration method. The calculated free-energy profile is applied to the coarse-grained potential of the effective interaction between two amino acid residues. The Langevin dynamics simulations with our coarse-grained potential are performed for association of a small protein complex, GCN4-pLI tetramer. The tetramer conformation reproduced by our coarse-grained model is similar to the X-ray crystallographic structure. We show that the effective interaction between charged amino acid residues stabilises association and orientation of protein complex. We also investigate the association pathways of GCN4-pLI tetramer.

Using force-based adaptive resolution simulations to calculate solvation free energies of amino acid sidechain analogues.

The calculation of free energy differences is a crucial step in the characterization and understanding of the physical properties of biological molecules. In the development of efficient methods to compute these quantities, a promising strategy is that of employing a dual-resolution representation of the solvent, specifically using an accurate model in the proximity of a molecule of interest and a simplified description elsewhere. One such concurrent multi-resolution simulation method is the Adaptive Resolution Scheme (AdResS), in which particles smoothly change their resolution on-the-fly as they move between different subregions. Before using this approach in the context of free energy calculations, however, it is necessary to make sure that the dual-resolution treatment of the solvent does not cause undesired effects on the computed quantities. Here, we show how AdResS can be used to calculate solvation free energies of small polar solutes using Thermodynamic Integration (TI). We discuss how the potential-energy-based TI approach combines with the force-based AdResS methodology, in which no global Hamiltonian is defined. The AdResS free energy values agree with those calculated from fully atomistic simulations to within a fraction of kBT. This is true even for small atomistic regions whose size is on the order of the correlation length, or when the properties of the coarse-grained region are extremely different from those of the atomistic region. These accurate free energy calculations are possible because AdResS allows the sampling of solvation shell configurations which are equivalent to those of fully atomistic simulations. The results of the present work thus demonstrate the viability of the use of adaptive resolution simulation methods to perform free energy calculations and pave the way for large-scale applications where a substantial computational gain can be attained.