Journal of Computational Biophysics and Chemistry

Aromatic amino acids (AAA) play a crucial role in the structure and function of proteins. A higher level of AAA causes several diseases, controls insulin levels. In this work, we carried out atomistic molecular dynamics simulations by using CHARMM Drude polarizable force field to investigate the conformational properties of insulin monomer in 2M phe, tyr, trp solutions as well as in pure aqueous solution to compare the relative changes of protein conformations, its solvation properties and the interactions of the free AAA with insulin. Although insulin’s native folded form was intact in all the solutions within the simulation length scale, we observed that the protein is a little more flexible and less compact in phe solution than in tyr/trp solutions. The free AAAs identified to self-aggregate around the protein surface and form clusters of different sizes. They interacted with insulin, significantly through cation/anion–π and π–π stacking, and partly through hydrogen bonded interactions. Among the three, trp was prone to interact through cation–π interactions while phe and tyr interacted through π–π stacking with insulin. Despite a significant number of free AAA molecules in the solvation shell, insulin was observed to be sufficiently hydrated and formed hydrogen bonds with water. Some of our findings agreed with the available experimental results that establish the reliability of the chosen force field. Our findings would interpret the interactions between the free AAA and insulin in solution, helpful to recognize the microscopic details of AAA governed biological processes in living organisms.

The correct reproduction of conformational substates of amino acids was tested for the CHARMM Drude polarizable force field. This was achieved by evaluating the reorganization energies for all low lying energy minima occurring in all 15 neutral blocked amino acids on a quantum-mechanical (QM) energy surface at the MP2/cc-pVDZ level. The results indicate that the bonded parameters of the N-acetyl (ACE) and N-Methylamide (CT3) blocking groups lead to significant discrepancies. A reparametrization of five bond angles significantly improved the agreement with the QM energy surface. The corrected Drude force field exhibits almost the same average reorganization energies relative to the MP2 energy surface as the AM1 and PM3 semi-empirical methods.

Polarizable molecular dynamics simulations are a fast progressing field in the scientific research of ionic liquids. The fundamentals of polarizable simulations, as well as their application to ionic liquids, were summarized in a review [Bedrov, D.; Piquemal, J.-P.; Borodin, O.; MacKerell, Jr., A. D.; Roux, B.; Schröder, C. Molecular Dynamics Simulations of Ionic Liquids and Electrolytes Using Polarizable Force Fields. Chem. Rev. 2019, 119, 7940–7995] in 2019. Since then, new methods to treat intermolecular interaction of induced dipoles in these highly charged systems were developed. This concerns the damping of these interactions and additional charge transfer as well as the prediction of ionic materials with ultrahigh refractive indices. In addition to the progress of the polarizable force fields, also thermostats and barostats for polarizable simulations evolved recently.

Bonded (or valence) interactions, which directly determine the local structures of the molecules, are fundamental parts of molecular mechanics force fields (FFs). Most popular classical FFs adopt the simple harmonic models for bond stretching and angle bending and ignore cross-coupling effects among the valence terms. This may lead to less accurate vibrational properties and configurations in molecular dynamics (MD) simulations. AMOEBA models utilize an MM3(MM4)-style bonded interaction model, in which the vibrational anharmonicity, the coupling effects among different energy terms, and the out-of-plane bending for sp2-hybridized atoms are considered. In this work, we report the development of bonded interaction parameters for a wide range of chemistry based on quantum mechanics (QM). About 270 atomic types defined by SMARTS strings were used to model the valence interactions. Our results indicate that the resulting valence parameters produce accurate vibrational frequencies (RMSD from QM is less than ∼36.6cm⁻¹) over a large set of molecules with diverse functional groups (445 molecules). By contrast, the harmonic models usually give an RMS error greater than 60cm⁻¹. Meanwhile, this model accurately reflects the potential energy surface of the out-of-plane bending. Our model can generally be applied to the AMOEBA family and any MM3(MM4)-based molecular mechanics FFs.

Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-$\beta$ oligomers and fibrils. The structural plasticity of amyloids leads to sampling of metastable, low-molecular-weight oligomers that contribute to cytotoxicity. Of interest are amyloid-$\beta$ (A$\beta$ and islet amyloid polypeptide (IAPP), which are involved in the pathology of Alzheimer’s disease and Type 2 diabetes mellitus, respectively. In addition to forming homogenous oligomers and fibrils, these species have been found to cross-aggregate in heterogeneous structures. Biophysical properties, including electronic effects, that are unique or conserved between homogenous and heterogeneous amyloids oligomers are thus far unexplored. Here, we simulated homogenous and heterogeneous amyloid oligomers of A${\beta }_{16-22}$ and IAPP${}_{20-29}$ fragments using the Drude oscillator model to investigate the impact of electronic polarization on the structural morphology and stability of preformed hexamers. Upon simulation of preformed, $\beta$-strand rich oligomers with Drude, structural rearrangement occurred causing some loss of $\beta$-strand structure in favor of random coil content for all oligomers. Homogenous A${\beta }_{16-22}$ was the most stable system, deriving stability from low polarization in hydrophobic residues and through salt bridge formation. Changes in polarization were observed primarily for A${\beta }_{16-22}$ residues in heterogeneous cross-amyloid systems, displaying a decrease in charged residue dipole moments and an increase in hydrophobic sidechain dipole moments. This work is the first study utilizing the Drude-2019 force field with amyloid oligomers, providing insight into the impact of electronic effects on oligomer structure and highlighting the importance of different microenvironments on amyloid oligomer stability.

Molecular dynamics (MD) simulations play a crucial role in modeling biomolecular systems in which the electrostatic interactions are critical in dictating the structural and dynamical properties. Thus, the treatment of the electrostatic interactions defined in the underlying force field (FF) strongly affects the simulation accuracy. Most FFs use fixed partial atomic charges to include electrostatic interactions, and therefore lack the electronic polarization response, representing an intrinsic limitation. To address this limitation, polarizable FFs have been developed that treat atomic polarizabilities explicitly. Here we present the application of the all-atom polarizable (Drude) and non-polarizable (CHARMM) nucleic acid FFs in RNA hairpin systems to investigate the impact of polarization on structural properties, dipole moment distributions, and cation interactions. Results show that the presence of polarizability in the FF significantly improves the stabilization of RNA hairpin structure. As expected, the distributions of dipole moments show more fluctuations when simulated using the polarizable FF, with the variation in dipoles contributing to the stabilization of the structures of the loop regions of the RNAs. Contact map analyses between the bases and cations show that the variation of the ion distribution around the entire hairpin is larger for the polarizable FF and the cations occupy the outer hydration shell to a greater extent. The presented results indicate the importance of the explicit treatment of electronic polarizability in molecular simulations of RNA, including in non-canonical regions.

Metal ions are ubiquitous in complex with proteins and play key roles in protein structure and function. The ion-protein interactions are electrostatic delicate in nature, however, the description of electrostatic interactions could be problematic in conventional additive fixed-charge force fields. With empowered computational sources going beyond the common approximations, many efforts have been done to take account in more elaborate electrostatic description in molecular modeling using more sophisticated physical models and dilated algorithms/implementations. Here we review rencent progress in advanced polarizable models and new impletment approaches towards accurate electrostatics and highlight some successful application cases in ion-protein interaction systems in recent years.

In this paper, we review both development and applications of the atom-bond electronegativity equalization method fused into molecular mechanics, i.e., ABEEM/MM polarizable force field (FF). We will focus on the applications of the ABEEM/MM in pure water systems, chemical and biomolecular ion-containing systems, small molecules and biomolecules, etc. The results show that the performance of ABEEM/MM is generally better than that of the commonly used nonpolarizable force fields.