Molecular dynamics simulation of amphiphilic aggregates

In this dissertation, molecular dynamics simulations were performed for systems containing amphiphilic aggregates, such as monolayers, bilayers, and reverse micelles. Various analysis methods were used in order to investigate structural and dynamical properties and solve particular problems for different systems. First, we present simulations where we observed successful self-assembly of reverse micelles in a three-component system containing supercritical CO2, water, and fluorinated surfactant starting from random configurations. Such self-assembly allows for the future computational study of structural and thermodynamic properties of microemulsions in water/CO2 systems that will be less dependent on the initial conditions. Next, a series of molecular dynamics simulations were performed to study the PFPE (perfluoropolyether) and PE (polyether) surfactant monolayers and micelles at the water/supercritical carbon dioxide interface. We observed that values of intramolecular bonded interaction parameters which are related to chain rigidity determine the monolayer surface pressure. We show that good and bad properties of PFPE/PE surfactants are connected to conformational entropy. In order to study the effect of the hydration force, we simulated systems with model hydrophilic plates. We studied the effect of charge correlation on the potential of mean force between plates. The orientational structure of water between the plates was investigated to understand the effect of molecular structure of water on the properties of the potential of mean force. Finally, we calculated the free energy cost for removing a cholesterol molecule from two different lipid bilayers. The results can help us to understand the relationship between the lipid structure and the lipid-cholesterol affinity. N-palmitoyl-sphingomyelin was found to have a better cholesterol affinity compared with that of phosphatidylcholine lipid DPPC, according to our free energy values from molecular dynamics simulations

Multiscale Coarse-Graining of the Protein Energy Landscape

A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states.</p

Multiscale Coarse-Graining of the Protein Energy Landscape

A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states

PRE data for "Structure Ensemble of the First Two RNA Recognition Motif Domains of a Poly(U) Binding Protein from Paramagnetic Relaxation Enhancement and Molecular Simulation"

<br> <p><b>Structure Ensemble of the First Two </b><b>RNA Recognition Motif</b><b> Domains of a Poly(U) Binding Protein from Paramagnetic Relaxation Enhancement and Molecular Simulation</b></p> <p><b> </b></p> <p>Guanhua Zhu¹, Wei Liu², Chenglong Bao³, Dudu Tong¹, Hui Ji³, Zuowei Shen³, Daiwen Yang², Lanyuan Lu^1*</p><p>^{Manuscript submitted for review.}</p

Multiscale Coarse-Graining via Normal Mode Analysis

A multiscale coarse-graining method called the normal-mode analysis based fluctuation matching (NMA-FM) is developed for constructing coarse-grained models of biomolecular systems. In the framework of normal-mode analysis, an arbitrary fine-grained model can be systematically converted to a more coarse-grained model, while the crucial low-frequency motions of the fine-grained system are able to be reproduced in the coarse-grained modeling. The method relies on the technique of fluctuation matching that has been devised earlier for parametrizing heterogeneous elastic network models based on data from atomistic molecular dynamics simulations. The new approach is quite efficient since it avoids expensive atomistic molecular dynamics simulations and can start from already coarse-grained elastic network models. In the practical aspect, the method is suitable for conformational analyses of large biomacromolecules and calculations of mechanical properties of biomaterials, which is demonstrated by the studied systems including an amyloid dimer, lysozyme and adenylate kinase proteins, and the S2 subdomain of myosin

Modeling solution X-ray scattering of biomacromolecules using an explicit solvent model and the fast Fourier transform

A novel computational method based on atomic form factors and the fast Fourier transform (FFT) is developed to compute small- and near-wide-angle X-ray scattering profiles of biomacromolecules from explicit solvent modeling. The method is validated by comparing the results with those from non-FFT approaches and experiments, and good agreement with experimental data is observed for both small and near-wide angles. In terms of computational efficiency, the FFT-based method is advantageous for protein solution systems of more than 3000 atoms. Furthermore, the computational cost remains nearly constant for a wide range of system sizes. The FFT-based approach can potentially handle much larger molecular systems compared with popular existing methods.MOE (Min. of Education, S’pore)Published versio

Multiscale Coarse-Graining via Normal Mode Analysis

A multiscale coarse-graining method called the normal-mode analysis based fluctuation matching (NMA-FM) is developed for constructing coarse-grained models of biomolecular systems. In the framework of normal-mode analysis, an arbitrary fine-grained model can be systematically converted to a more coarse-grained model, while the crucial low-frequency motions of the fine-grained system are able to be reproduced in the coarse-grained modeling. The method relies on the technique of fluctuation matching that has been devised earlier for parametrizing heterogeneous elastic network models based on data from atomistic molecular dynamics simulations. The new approach is quite efficient since it avoids expensive atomistic molecular dynamics simulations and can start from already coarse-grained elastic network models. In the practical aspect, the method is suitable for conformational analyses of large biomacromolecules and calculations of mechanical properties of biomaterials, which is demonstrated by the studied systems including an amyloid dimer, lysozyme and adenylate kinase proteins, and the S2 subdomain of myosin

Conformational states of Zika virus non-structural protein 3 determined by molecular dynamics simulations with small-angle X-Ray scattering data

Zika virus (ZIKV) has become a great public health emergency. Its non-structural protein 3 (NS3) is a key enzyme in viral replication and has been considered as a potential therapeutic target. A conformational characterization of ZIKV NS3 is critical for a comprehensive understanding of its molecular interactions and functions. However, the high conformational flexibility of solution NS3 obstacles the structural characterization of NS3 solely from the experimental observable that averages over its heterogeneous conformations. Here, we employed replica exchange with solute tempering (REST) method to simulate the di-domain protein ZIKV NS3. Three independent MD simulations identified a conserved conformational ensemble of NS3, consisting of a major conformational state and several minor states from compact to loose conformations. The major state agrees well with the scattering profile from small-angle X-ray scattering (SAXS) experiments. Moreover, the simulated ensemble is supported by a direct data-fitting result that requires both short- and long-range structural contacts to recover the experimental data. We discussed the interplay between simulation and experiment in ensemble construction of flexible biomolecules and shed light on the physically derived conformational ensembles.Ministry of Education (MOE)This research is supported by the Tier 3 grant (MOE2012-T3-1- 008) from the Ministry of Education, Singapore