Molecular simulations of conformational transitions in biomolecules using a novel computational tool

The function of biological macromolecules is inherently linked to their complex conformational behaviour. As a consequence, the corresponding potential energy landscape encompasses multiple minima. Some of the intermediate structures between the initial and final states can be characterized by experimental techniques. Computer simulations can explore the dynamics of individual states and bring these together to rationalize the overall process. A novel method based on atomistic structure-based potentials in combination with the empirical valence bond theory (EVB-SBP) has been developed and implemented in the Amber package. The method has been successfully applied to explore various biological processes. The first application of the EVB-SBP approach involves the study of base flipping in B-DNA. The use of simple structurebased potentials are shown to reproduce structural ensembles of stable states obtained by using more accurate force field simulations. Umbrella sampling in conjunction with the energy gap reaction coordinate enables the study of alternative molecular pathways efficiently. The main application of the method is the study of the switching mechanism in a short bistable RNA. Molecular pathways, which connect the two stable states, have been elucidated, with particular interest to the characterisation of the transition state ensemble. In addition, NMR experiments have been performed to support the theoretical findings. Finally, a recent study of large-scale conformational transitions in protein kinases shows the general applicability of the method to different biomolecules

Structure Property and Prediction of Novel Materials using Advanced Molecular Dynamics Techniques: Novel Carbons, Germaniums and High-Performance Thermoelectrics

By means of advanced molecular dynamic techniques, we predict the stability of novel materials based on carbon, germanium and PbSe. This topological solutions have been studied and characterised at a DFT/DFTB level of theory and interesting optical, mechanical, electronic and heat transport properties have been pointed out

Advances in Molecular Simulation

Molecular simulations are commonly used in physics, chemistry, biology, material science, engineering, and even medicine. This book provides a wide range of molecular simulation methods and their applications in various fields. It reflects the power of molecular simulation as an effective research tool. We hope that the presented results can provide an impetus for further fruitful studies

2005 American Conference on Theoretical Chemistry

The materials uploaded are meant to serve as final report on the funds provided by DOE-BES to help sponsor the 2005 American Conference on Theoretical Chemistry

Understanding fluorescent amyloid biomarkers by computational chemistry

Protein misfolding diseases, including neurodegenerative disorders like Alzheimer’s disease, are characterized by the involvement of amyloid aggregation, which emphasizes the need for molecular biomarkers for effective disease diagnosis. The thesis addresses two aspects of biomarker development: firstly, the computation of vibrationally resolved spectra of small fluorescent dyes to detect amyloid aggregation, and secondly, the binding and unbinding processes of a novel ligand to the target protein. In relation to the first aspect, a hybrid model for vibrational line shapes of optical spectra, called VCI-in-IMDHO, is introduced. This model enables the treatment of selected modes using highly accurate and anharmonic vibrational wave function methods while treating the remaining modes using the approximate IMDHO model. This model reduces the computational cost and allows for the calculation of emission line shapes of organic dyes with anharmonicity in both involved electronic states. The interaction between the dyes and their environment is also explored to predict the photophysical properties of the oxazine molecules in the condensed phase. The position and the choice of the solvent molecule have a significant impact on the spectra of the studied systems as they altered the spectral band shape. However, further studies are necessary to confirm the findings. In addition to neurodegenerative diseases, the systemic amyloidoses represent another group of disorders caused by misfolded or misassembled proteins. In the cardiac domain, the accumulation of amyloid fibrils formed by the transthyretin (TTR) protein leads to cardiac dysfunction and restrictive cardiomyopathy. The investigation of binding and unbinding pathways between the TTR protein and its ligands is crucial for gaining a comprehensive understanding and enabling early detection of systemic amyloidoses and related disorders. Hence, exploring the different binding modes and the dissociation pathways of TTR-ligand complex is the primary objective of the second aspect of this thesis. The experimental study provides evidence of binding and X-ray crystallographic structure data on TTR complex formation with the fluorescent salicylic acid-based pyrene amyloid ligand (Py1SA). However, the electron density from X-ray diffraction did not allow confident placement of Py1SA, possibly due to partial ligand occupancy. Molecular dynamics and umbrella sampling approaches were used to determine the preferred orientation of the Py1SA ligand in the binding pocket, with a distinct preference for the binding modes with the salicylic acid group pointing into the pocket.Deutsche Forschungs-gemeinschaft (DFG)/Emmy Noether/KO 5423/1- 1/E

First Principles Investigations of Novel Condensed Matter Materials

The advent of very fast computing power has led to the positioning of theoretical investigations of condensed matter materials as a core part of research in this area. Often the results of such numerical and computational investigations serve as reliable guide for future experimental exploration of new materials and has led to the discovery of numerous materials. In this thesis, state-of-the-art first principles calculations have been applied to investigate the structural, electronic and dynamical properties of some novel condensed matter materials. The novelty of these compounds stems from the fact that they challenge our previous knowledge of the chemistry of chemical reactions that support the formation and stability of chemical compounds and can therefore expand our frontier of knowledge in the quest for scientific understanding of new atypical compounds in high pressure physics. In the first project, the long sought post-Cmcm phase of the cadmium telluride is characterized with the application of first principles metadynamics method. It has a monoclinic unit cell and the P21/m space group. Enthalpy calculation confirms this phase transition sequence and further predicts a P21/m to P4/nmm transition near 68 GPa. Interestingly, the enthalpies of CdTe compounds are found to be higher than the enthalpy sum of its constituents Cd and Te at pressures higher than 34 GPa which is an indication that the com-pound should decompose above this pressure point. However, dynamical stability revealed in the phonon dispersion relations prevents the decomposition of CdTe at high pressure. This suggests that CdTe becomes a high-enthalpy compound at high pressure. The second project is directed towards the prediction of stable helium-hydrogen compound. In spite of extensive experimental and theoretical work, a general agreement on the crystal structure and stability of the helium-hydrogen system is lacking. In this study, the possibility of helium forming stable compound with hydrogen is investigated by using first principles structure search method. A stable helium hydrogen compound formed at ambient conditions is found. It belongs to the triclinic P-1 space group, having He(H2)3stoichiometry. Topological analysis of electron density at the bond critical points shows there exists a quantifiable level of bonding interaction between helium and hydrogen in the P-1 structure. At ambient pressure, the compound is characterized and stabilized by interactions with strength typical of van der Waals interaction that increases with pressure. This current results provide a case of weak interaction in a mixed hydrogen-helium system, offering insights for the evolution of interiors of giant planets such as Jupiter and Saturn. In the final project, a machine learning potential is successfully created for sodium based on the Gaussian process regression method and weighted atom-centered symmetry functions representation of the potential energy surface. Here, sodium potential energy surface is described using different relevant data sets that represent several regions of the potential energy surface with each data set consisting of three element groups which are total energies, inter-atomic forces, and stress tensors of the cell, which were constructed from density functional theory calculations. It is demonstrated that by learning from the underlying density functional theory results, the trained machine learning potential is able to reproduce important properties of all available sodium phases with an exceptional accuracy in comparison to those computed using density functional theory. In combination with the metadynamics method, this well trained machine learning potential is applied to large simulation boxes containing1024 and 3456 sodium atoms in the cI16 phase. These large-scale simulations reveal a notable phase transition at 150 K and 120 GPa with an impressive capturing of the rearrangements of atomic configurations involved in the transition process that may not be evident in asmall-scale simulation. Without a doubt, this work shows that applying machine learning methods to condensed matter systems will lead to significant increase in our understanding of important processes such as atomic rearrangements, growth and nucleation process in crystal formation and phase transition

Conformational equilibria and spectroscopy of gas-phase homologous peptides from first principles

Peptides and proteins fulfil crucial tasks enabling and maintaining life. Their function is directly correlated with their three-dimensional structure, which is in turn determined by their chemical composition, the amino-acid sequence. Predicting the structure of a peptide based only on its sequence information is of fundamental interest. A fully first-principles treatment free of empirical parameters would be ideal. However, this presents an ongoing challenge, due to the large system size and conformational space of most peptides. In the present work, we address this challenge concentrating on the example of polyalanine-based peptides in the gas phase. Such studies under isolated conditions follow a bottom-up approach that allows one to investigate the intramolecular interactions important for secondary structure separate from environmental effects. Furthermore, direct benchmarks of theoretical structure predictions against experiment are facilitated. The peptide series Ac-Alan-Lys(H+), (n > 6), forms α-helices in the gas phase due to a favorable interaction of the helix dipole with the positive charge at the C-terminal lysine residue. Using this design principle as a template, we explore the impact of increased structural flexibility on the conformational space due to (i) sequence length [Ac-Alan-Lys(H+), n = 19], (ii) charge placement [Ac-Ala19-Lys(H+) versus Ac-Lys(H+)-Ala19], and (iii) backbone elongation of the monomer units as represented by β-amino acids [Ac-β2hAla6-Lys(H+)]. To address the large conformational space, we develop a three-step structure-search strategy employing an unprecedented first-principles screening effort. After pre-sampling of the conformational space using a force field, thousands of structures are optimized employing density-functional theory (DFT). For this, the PBE functional is used, coupled with a pairwise correction for van der Waals interactions. For the best few structure candidates, ab initio replica-exchange molecular-dynamics simulations are performed in order to refine the local structural environment. It is shown that these can yield lower-energy conformations and lead to rearrangements of the hydrogen-bonding network. In order to connect to experiment, collision cross sections are calculated that link to ion mobility-mass spectrometry. Furthermore, infrared spectra are derived from ab initio Born-Oppenheimer molecular-dynamics simulations accounting for anharmonicities within the classical-nuclei approximation. As expected, the 20-residue peptide Ac-Ala19-Lys(H+) forms helical structures. In contrast, placing the charge at the N-terminus [Ac-Lys(H+)-Ala19], leads to several different compact structures, which are close in energy. Such small energy differences present a challenge to the theoretical approach. Incorporating exact exchange and many-body van der Waals effects predicts the presence of only one dominant conformer, which is compatible with both experimental datasets. In comparison to Ac-Ala6-Lys(H+), the β-peptide Ac-β2hAla6-Lys(H+) exhibits increased conformational flexibility due to an extended monomer backbone. Out of the almost 15,000 structures optimized with DFT, no helical conformers are found in the low-energy regime. This is changed when considering vibrational free energy (300K, harmonic approximation), which strongly favors helical conformations due to softer vibrational modes. One possible structure candidate is the H16-helix, which is compatible with both experiments. It is a unique structure as it exhibits a hydrogen-bonding pattern equivalent to the helix of natural peptides. The systems considered here highlight the advances of current DFT functionals to address the large conformational space of peptides, but also the need for further development

New experimental and theoretical tools for studying protein systems with elements of structural disorder

Disordered proteins are one class of proteins which do not possess well-folded three-dimensional structures as their native conformations. Many eukaryotic proteins have been found to be fully disordered or contain certain disordered regions. Disordered proteins usually display several characteristic properties, such as increased motional freedom and the conformational heterogeneity caused by that. The elements of structural disorder are commonly involved in many important biological functions and are implicated in many diseases. Therefore, the study of disordered proteins has become one of the most important research topics in recent years. This thesis presents results from three different research projects; the common feature is that all systems being studied contain varying amount of structural disorder. Most results have been obtained based on experimental nuclear magnetic resonance (NMR) studies and molecular dynamics (MD) simulations. Both are among the most popular biophysical techniques for studying molecular dynamics. The first project investigates the relationship between domain cooperativity and residual dipolar coupling (RDC) parameters based on a series of two-domain chimera proteins with disordered linkers. Many eukaryotic proteins contain multiple domains and their biological functions are closely related to the property of domain cooperativity, which is often regulated by the linker region. Therefore it is necessary to develop suitable tools to characterize linker region properties in order to better understand biological functions of multidomain proteins. The second project is about the development of NMR pulse sequences for studying disordered proteins. Two new NMR pulse sequences, PD-CPMG and CP-HISQC, have been developed. Both experiments are well suited for studying intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) under physiological conditions. These two experiments produce higher precision for 15N R2 rates measurement or higher sensitivity in 1H– 15N HSQC spectra respectively. Besides, they also show many advantages over most other existing experiments for studying IDPs. The last project is about protein-peptide encounter complex study based on Crk-Sos model system. The ten-residue Sos peptide serves as a minimal model for disordered proteins. Encounter complex is an important type of intermediate state formed during many protein interactions. Such complexes are usually characterized by a large amount of motional freedom and conformational heterogeneity. Therefore their properties are considerably different from tight-binding complexes which are more commonly studied. Although it is usually quite difficult to study encounter complexes using standard biophysical techniques, in this project we have successfully characterized structural and dynamic properties of Crk-Sos electrostatic encounter complex with a combination of MD simulations and experimental NMR approaches. It can be directly seen from the structural model based on MD trajectories that Sos peptide in the encounter complex remains highly dynamic, sampling large area on the surface of Crk N-SH3 domain. Such strategy can also be utilized for studying many other encounter complexes involving disordered proteins or peptide