A multiscale coarse‐grained polarizable solvent model for handling long tail bulk electrostatics

A multiscale coarse‐grained approach able to handle efficiently the solvation of microscopic solutes in extended chemical environment is described. That approach is able to compute readily and efficiently very long‐range solute/solvent electrostatic microscopic interactions, up to the 1‐μm scale, by considering a reduced amount of computational resources. All the required parameters are assigned to reproduce available data concerning the solvation of single ions. Such a strategy makes it possible to reproduce with good accuracy the solvation properties concerning simple ion pairs in solution (in particular, the asymptotic behavior of the ion pair potentials of mean force). This new method represents an extension of the polarizable pseudoparticle solvent model, which has been recently improved to account for the main features of hydrophobic effects in liquid water (Masella et al., J. Comput. Chem. 2011 , 32, 2664). This multiscale approach is well suited to be used for computing the impact of charge changes in free energy computations, in terms of both accuracy and efficiency. © 2013 Wiley Periodicals, Inc.     

Reconstruction of atomistic details from coarse‐grained structures

We present an algorithm to reconstruct atomistic structures from their corresponding coarse‐grained (CG) representations and its implementation into the freely available molecular dynamics (MD) program package GROMACS. The central part of the algorithm is a simulated annealing MD simulation in which the CG and atomistic structures are coupled via restraints. A number of examples demonstrate the application of the reconstruction procedure to obtain low‐energy atomistic structural ensembles from their CG counterparts. We reconstructed individual molecules in vacuo (NCQ tripeptide, dipalmitoylphosphatidylcholine, and cholesterol), bulk water, and a WALP transmembrane peptide embedded in a solvated lipid bilayer. The first examples serve to optimize the parameters for the reconstruction procedure, whereas the latter examples illustrate the applicability to condensed‐phase biomolecular systems. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2010     

A new algorithm for construction of coarse‐grained sites of large biomolecules

The development of coarse‐grained (CG) models for large biomolecules remains a challenge in multiscale simulations, including a rigorous definition of CG representations for them. In this work, we proposed a new stepwise optimization imposed with the boundary‐constraint (SOBC) algorithm to construct the CG sites of large biomolecules, based on the s cheme of essential dynamics CG. By means of SOBC, we can rigorously derive the CG representations of biomolecules with less computational cost. The SOBC is particularly efficient for the CG definition of large systems with thousands of residues. The resulted CG sites can be parameterized as a CG model using the normal mode analysis based fluctuation matching method. Through normal mode analysis, the obtained modes of CG model can accurately reflect the functionally related slow motions of biomolecules. The SOBC algorithm can be used for the construction of CG sites of large biomolecules such as F‐actin and for the study of mechanical properties of biomaterials. © 2015 Wiley Periodicals, Inc.     

An anisotropic coarse‐grained model based on Gay–Berne and electric multipole potentials and its application to simulate a DMPC bilayer in an implicit solvent model

In this work, we aim at optimizing the performance of the anisotropic GBEMP model, which adopts a framework by combining a Gay–Berne (GB) anisotropic potential with an electric multipole (EMP) potential, in simulating a DMPC lipid bilayer in an implicit solvent model. First, the Gay–Berne parameters were initially obtained by fitting to atomistic profiles of van der Waals interactions between homodimers of molecular fragments while EMP parameters was directly derived from the expansion of point multipoles at predefined EMP sites. Second, the GB and EMP parameters for DMPC molecule were carefully optimized to be comparable to AMBER atomistic model in the calculations of the dipole moments of DMPC monomers adopting different conformations as well as the nonbonded interactions between two DMPC molecules adopting different conformations and separated at various distances. Finally, the GB parameters for DMPC were slightly adjusted in simulating a 72 DMPC bilayer system so that our GBEMP model would be able to reproduce a few important structural properties, namely, thickness (), area per lipid ( ) and volume per lipid ( ). Meanwhile, the atomistic and experimental results for electron density profiles and order parameters were reproduced reasonably well by the GBEMP model, demonstrating the promising feature of GBEMP model in modeling lipid systems. Finally, we have shown that current GBEMP model is more efficient by a factor of about 25 than AMBER atomistic point charge model. © 2015 Wiley Periodicals, Inc.     

A coarse‐grained MARTINI‐like force field for DNA unzipping in nanopores

In nanopore force spectroscopy (NFS) a charged polymer is threaded through a channel of molecular dimensions. When an electric field is applied across the insulating membrane, the ionic current through the nanopore reports on polymer translocation, unzipping, dissociation, and so forth. We present a new model that can be applied in molecular dynamics simulations of NFS. Although simplified, it does reproduce experimental trends and all‐atom simulations. The scaled conductivities in bulk solution are consistent with experimental results for NaCl for a wide range of electrolyte concentrations and temperatures. The dependence of the ionic current through a nanopore on the applied voltage is symmetric and, in the voltage range used in experiments (up to 2 V), linear and in good agreement with experimental data. The thermal stability and geometry of DNA is well represented. The model was applied to simulations of DNA hairpin unzipping in nanopores. The results are in good agreement with all‐atom simulations: the scaled translocation times and unzipping sequence are similar. © 2015 Wiley Periodicals, Inc.     

Prediction of viscoelastic properties with coarse‐grained molecular dynamics and experimental validation for a benchmark polyurea system

To explore the relationship between microscopic structure and viscoelastic properties of polyurea, a coarse‐grained (CG) model is developed by a structure matching method and validated against experiments conducted on a controlled, benchmark material. Using the Green‐Kubo method, the relaxation function is computed from the autocorrelation of the stress tensor, sampled over equilibrium MD simulations, and mapped to a real time scale established by matching self‐diffusion rates of atomistic and CG models. Master curves computed from the predicted stress relaxation function are then compared with dynamic mechanical analysis experiments mapped to a wide frequency range by time–temperature superposition, as well as measurements of ultrasonic shear wave propagation. Computational simulations from monodisperse and polydisperse configurations, representative of the benchmark polyurea, show excellent agreement with the experimental measurements over a multidecade range of loading frequency. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 797–810     

Melting thermodynamics of oligonucleic acids conjugated with relatively solvophobic linear polymers: A coarse‐grained molecular simulation study

Oligonucleic acids (ONAs), such as DNA and RNA, are used in various biotechnology and nanotechnology applications due to their ability to form a double helix that is stable at low temperature and melts at high temperatures. The melting temperature (T_m) of ONA duplexes can be tuned by the ONA composition, sequence, length and concentration, solvent quality, and salt concentration and by conjugation to other macromolecules. In this article, we use coarse‐grained (CG) molecular simulations to study ONAs conjugated with linear homopolymers that are relatively more solvophobic than the ONA. We study charged and stiff 8‐mer ONAs (e.g., DNA) and neutral and flexible 8‐mer ONAs (e.g., peptide nucleic acids or PNA), and vary the composition (or G‐C content) and sequence of ONA, conjugated homopolymer lengths and solvent quality for the polymer. For neutral and flexible ONAs, as the solvent quality worsens for the polymer, the ONA melting temperature increases from that of unconjugated ONA. The melting curves broaden with polymer length and worsening solvent quality, especially for ONAs with higher G‐C content. For charged and stiff ONAs, as the solvent quality worsens, the ONA melting temperature decreases compared to unconjugated ONA while the width of the melting curve remains the same. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019 , 57, 1196–1208     

Implicit solvent coarse‐grained model of polyamidoamine dendrimers: Role of generation and pH

Highly branched polymers such as polyamidoamine (PAMAM) dendrimers are promising macromolecules in the realm of nanobiotechnology due to their high surface coverage of tunable functional groups. Modeling efforts of PAMAM can provide structural and morphological properties, but the inclusion of solvents and the exponential growth of atoms with generations make atomistic simulations computationally expensive. We apply an implicit solvent coarse‐grained model, called the Dry Martini force field, to PAMAM dendrimers. The reduced number of particles and the absence of a solvent allow the capture of longer spatiotemporal scales. This study characterizes PAMAM dendrimers of generations one through seven in acidic, neutral, and basic pH environments. Comparison with existing literature, both experimental and theoretical, is done using measurements of the radius of gyration, moment of inertia, radial distributions, and scaling exponents. Additionally, ion coordination distributions are studied to provide insight into the effects of interior and exterior protonation on counter ions. This model serves as a starting point for future designs of larger functionalized dendrimers. © 2015 Wiley Periodicals, Inc.     

Exploring the parameter space of the coarse‐grained UNRES force field by random search: Selecting a transferable medium‐resolution force field

We explored the energy‐parameter space of our coarse‐grained UNRES force field for large‐scale ab initio simulations of protein folding, to obtain good initial approximations for hierarchical optimization of the force field with new virtual‐bond‐angle bending and side‐chain‐rotamer potentials which we recently introduced to replace the statistical potentials. 100 sets of energy‐term weights were generated randomly, and good sets were selected by carrying out replica‐exchange molecular dynamics simulations of two peptides with a minimal α‐helical and a minimal β‐hairpin fold, respectively: the tryptophan cage (PDB code: 1L2Y) and tryptophan zipper (PDB code: 1LE1). Eight sets of parameters produced native‐like structures of these two peptides. These eight sets were tested on two larger proteins: the engrailed homeodomain (PDB code: 1ENH) and FBP WW domain (PDB code: 1E0L); two sets were found to produce native‐like conformations of these proteins. These two sets were tested further on a larger set of nine proteins with α or α + β structure and found to locate native‐like structures of most of them. These results demonstrate that, in addition to finding reasonable initial starting points for optimization, an extensive search of parameter space is a powerful method to produce a transferable force field. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Polarizable coarse‐grained models for molecular dynamics simulation of liquid cyclohexane

Force field parameters for polarizable coarse‐grained (CG) supra‐atomic models of liquid cyclohexane are proposed. Two different bead sizes were investigated, one representing two fine‐grained (FG) CH₂r united atoms of the cyclohexane ring, and one representing three FG CH₂r united atoms. Electronic polarizability is represented by a massless charge‐on‐spring particle connected to each CG bead. The model parameters were calibrated against the experimental density and heat of vaporization of liquid cyclohexane, and the free energy of cyclohexane hydration. Both models show good agreement with thermodynamic properties of cyclohexane, yet overestimate the self‐diffusion. The dielectric properties of the polarizable models agree very well with experiment. © 2015 Wiley Periodicals, Inc.     

CHARMM‐GUI Martini Maker for modeling and simulation of complex bacterial membranes with lipopolysaccharides

A complex cell envelope, composed of a mixture of lipid types including lipopolysaccharides, protects bacteria from the external environment. Clearly, the proteins embedded within the various components of the cell envelope have an intricate relationship with their local environment. Therefore, to obtain meaningful results, molecular simulations need to mimic as far as possible this chemically heterogeneous system. However, setting up such systems for computational studies is far from trivial, and consequently the vast majority of simulations of outer membrane proteins still rely on oversimplified phospholipid membrane models. This work presents an update of CHARMM‐GUI Martini Maker for coarse‐grained modeling and simulation of complex bacterial membranes with lipopolysaccharides. The qualities of the outer membrane systems generated by Martini Maker are validated by simulating them in bilayer, vesicle, nanodisc, and micelle environments (with and without outer membrane proteins) using the Martini force field. We expect this new feature in Martini Maker to be a useful tool for modeling large, complicated bacterial outer membrane systems in a user‐friendly manner. © 2017 Wiley Periodicals, Inc.     

Introduction of steered molecular dynamics into UNRES coarse‐grained simulations package

In this article, an implementation of steered molecular dynamics (SMD) in coarse‐grain UNited RESidue (UNRES) simulations package is presented. Two variants of SMD have been implemented: with a constant force and a constant velocity. The huge advantage of SMD implementation in the UNRES force field is that it allows to pull with the speed significantly lower than the accessible pulling speed in simulations with all‐atom representation of a system, with respect to a reasonable computational time. Therefore, obtaining pulling speed closer to those which appear in the atomic force spectroscopy is possible. The newly implemented method has been tested for behavior in a microcanonical run to verify the influence of introduction of artificial constrains on keeping total energy of the system. Moreover, as time dependent artificial force was introduced, the thermostat behavior was tested. The new method was also tested via unfolding of the Fn3 domain of human contactin 1 protein and the I27 titin domain. Obtained results were compared with Gø‐like force field, all‐atom force field, and experimental results. © 2017 Wiley Periodicals, Inc.     

Efficient estimation of binding free energies between peptides and an MHC class II molecule using coarse‐grained molecular dynamics simulations with a weighted histogram analysis method

We estimate the binding free energy between peptides and an MHC class II molecule using molecular dynamics (MD) simulations with the weighted histogram analysis method (WHAM). We show that, owing to its more thorough sampling in the available computational time, the binding free energy obtained by pulling the whole peptide using a coarse‐grained (CG) force field (MARTINI) is less prone to significant error induced by inadequate‐sampling than using an atomistic force field (AMBER). We further demonstrate that using CG MD to pull 3–4 residue peptide segments while leaving the remaining peptide segments in the binding groove and adding up the binding free energies of all peptide segments gives robust binding free energy estimations, which are in good agreement with the experimentally measured binding affinities for the peptide sequences studied. Our approach thus provides a promising and computationally efficient way to rapidly and reliably estimate the binding free energy between an arbitrary peptide and an MHC class II molecule. © 2017 Wiley Periodicals, Inc.     

Coarse‐grained molecular dynamics simulations of protein–ligand binding

Coarse‐grained molecular dynamics (CGMD) simulations with the MARTINI force field were performed to reproduce the protein–ligand binding processes. We chose two protein–ligand systems, the levansucrase–sugar (glucose or sucrose), and LinB–1,2‐dichloroethane systems, as target systems that differ in terms of the size and shape of the ligand‐binding pocket and the physicochemical properties of the pocket and the ligand. Spatial distributions of the Coarse‐grained (CG) ligand molecules revealed potential ligand‐binding sites on the protein surfaces other than the real ligand‐binding sites. The ligands bound most strongly to the real ligand‐binding sites. The binding and unbinding rate constants obtained from the CGMD simulation of the levansucrase–sucrose system were approximately 10 times greater than the experimental values; this is mainly due to faster diffusion of the CG ligand in the CG water model. We could obtain dissociation constants close to the experimental values for both systems. Analysis of the ligand fluxes demonstrated that the CG ligand molecules entered the ligand‐binding pockets through specific pathways. The ligands tended to move through grooves on the protein surface. Thus, the CGMD simulations produced reasonable results for the two different systems overall and are useful for studying the protein–ligand binding processes. © 2014 Wiley Periodicals, Inc.     

LEAP: Highly accurate prediction of protein loop conformations by integrating coarse‐grained sampling and optimized energy scores with all‐atom refinement of backbone and side chains

Prediction of protein loop conformations without any prior knowledge (ab initio prediction) is an unsolved problem. Its solution will significantly impact protein homology and template‐based modeling as well as ab initio protein‐structure prediction. Here, we developed a coarse‐grained, optimized scoring function for initial sampling and ranking of loop decoys. The resulting decoys are then further optimized in backbone and side‐chain conformations and ranked by all‐atom energy scoring functions. The final integrated technique called loop prediction by energy‐assisted protocol achieved a median value of 2.1 Å root mean square deviation (RMSD) for 325 12‐residue test loops and 2.0 Å RMSD for 45 12‐residue loops from critical assessment of structure‐prediction techniques (CASP) 10 target proteins with native core structures (backbone and side chains). If all side‐chain conformations in protein cores were predicted in the absence of the target loop, loop‐prediction accuracy only reduces slightly (0.2 Å difference in RMSD for 12‐residue loops in the CASP target proteins). The accuracy obtained is about 1 Å RMSD or more improvement over other methods we tested. The executable file for a Linux system is freely available for academic users at http://sparks‐lab.org . © 2013 Wiley Periodicals, Inc.     

Comparing normal modes across different models and scales: Hessian reduction versus coarse‐graining

Dimension reduction is often necessary when attempting to reach longer length and time scales in molecular simulations. It is realized by constraining degrees of freedom or by coarse‐graining the system. When evaluating the accuracy of a dimensional reduction, there is a practical challenge: the models yield vectors with different lengths, making a comparison by calculating their dot product impossible. This article investigates mapping procedures for normal mode analysis. We first review a horizontal mapping procedure for the reduced Hessian techniques, which projects out degrees of freedom. We then design a vertical mapping procedure for the “implosion” of the all‐atom (AA) Hessian to a coarse‐grained scale that is based upon vibrational subsystem analysis. This latter method derives both effective force constants and an effective kinetic tensor. Next, a series of metrics is presented for comparison across different scales, where special attention is given to proper mass‐weighting. The dimension‐dependent metrics, which require prior mapping for proper evaluation, are frequencies, overlap of normal mode vectors, probability similarity, Hessian similarity, collectivity of modes, and thermal fluctuations. The dimension‐independent metrics are shape derivatives, elastic modulus, vibrational free energy differences, heat capacity, and projection on a predefined basis set. The power of these metrics to distinguish between reasonable and unreasonable models is tested on a toy alpha helix system and a globular protein; both are represented at several scales: the AA scale, a Gō‐like model, a canonical elastic network model, and a network model with intentionally unphysical force constants. Published 2012 Wiley Periodicals, Inc.