Conformational isomerism

In chemistry, conformational isomerism is a form of stereoisomerism in which the isomers can be interconverted just by rotations about formally single bonds (refer to figure on single bond rotation). While any two arrangements of atoms in a molecule that differ by rotation about single bonds can be referred to as different conformations, conformations that correspond to local minima on the potential energy surface are specifically called conformational isomers or conformers. Conformations that correspond to local maxima on the energy surface are the transition states between the local-minimum conformational isomers. Rotations about single bonds involve overcoming a rotational energy barrier to interconvert one conformer to another. If the energy barrier is low, there is free rotation and a sample of the compound exists as a rapidly equilibrating mixture of multiple conformers; if the energy barrier is high enough then there is restricted rotation, a molecule may exist for a relative

Characterization and prediction of peptide structures on inorganic surfaces

Dmitrii Maksimov

Interfaces between peptides and metallic surfaces are the subject of great interest for possible use in technological and medicinal applications, mainly since organic systems present an extensive range of functionalities, are abundant, cheap, and exhibit low toxicity. Exemplary applications are biosensors that may be sensitive to specific metabolites or harmful compounds. However, these hybrid interfaces pose a challenge to computational modelling, particularly regarding predicting the most relevant configurations at the surface, which determines the electronic properties of the system as a whole. From a theoretical point of view, predicting the most stable interface configuration requires searching through the enormous structure space of flexible biomolecules with respect to the surface for different configurations and performing computational calculations of their properties. However, it is impossible to investigate those parts separately due to complex interactions during adsorption. In order to capture these complex interactions, one has to employ accurate theoretical methods, which are very computationally expensive. In this thesis, we provide a comprehensive description of the complex nature of the interaction of selected amino acids with metallic surfaces using state-of-the-art dimensionality reduction techniques and accurate ab initio theoretical methods and creation of tools tailored for the high-throughput investigations of interface systems. The theoretical methods used in the thesis are described in the first part of the thesis. The second section looks into the conformational space changes of Arginine (Arg) and its protonated counterpart after adsorption on three noble metallic surfaces. Arg is an excellent testbed because it is tiny enough to be treated using density functional theory, which is considered the best compromise between accuracy and computational efficiency. At the same time, Arg is complex enough due to a highly flexible side-chain that allows for hundreds of different configurations in the gas phase alone. The examination of adsorption behavior requires creating a database by performing a large number of geometry optimizations of various conformations and orientations. The investigation of that database includes creating a low-dimensional representation of the conformational spaces using recent dimensionality reduction techniques, followed by examining various bonding and charge transfer patterns and how they affect the available conformational spaces.The third section of the thesis is concerned with developing tools for the automated structure search of interface systems and the modelling of self-assembly patterns formed after adsorption. Different geometry optimization algorithms and a flexible method of preconditioning the quasi-Newton optimization algorithms are implemented in the GenSec package that was developed. Together, these enable a more straightforward interface with a wide range of quantum chemistry packages for sampling the conformational spaces of flexible molecules in 1D (ions), 2D (surfaces), and 3D (cavities and molecules) systems. Structure search of the conformational space of a flexible molecule using GenSec provided satisfactory results for di-L-alanine adsorbed on Cu(110) surface.

EPFL2022

Amplitude and phase reconstruction for Low-Energy Electron Holography of individual proteins

Hannah Julia Ochner

Single-molecule imaging methods are of importance in structural biology, and specifically in the imaging of proteins, since they can elucidate conformational variability and structural changes that might be lost in imaging methods relying on averaging processes. Low-energy electron holography (LEEH) is a promising technique for imaging individual proteins with negligible radiation damage, which can be combined with a sample preparation process by native electrospray ion beam deposition (native ES-IBD) ensuring the creation of chemically pure samples suitable for holographic imaging.The central step in the analysis of data measured by LEEH is the numerical reconstruction of the object from the experimentally acquired holograms.Full information about the imaged object consists of both amplitude and phase information imprinted on the scattered wave during the interaction of the electron beam with the molecule and encoded in the hologram created by the interference of the scattered wave and the transmitted incident wave. A propagation-based algorithm with the goal of reconstructing the wave field in the plane of the object is presented and applied to holograms of individual proteins prepared by ES-IBD and measured with a low-energy electron holography microscope. The information retrieved from the reconstruction of the amplitude distribution in the object plane is discussed by analysing holograms of antibodies, demonstrating that the inherent conformational variability of these molecules can be mapped by LEEH. The influence of the sample preparation process on the surface conformations is tracked by tuning the landing energy of the proteins during deposition.To complement the amplitude data, an iterative phase retrieval algorithm is implemented to reconstruct the phase distribution in the object plane along with the amplitude distribution. The algorithm's performance and robustness is thoroughly evaluated and simulations regarding multiple scattering effects and element-dependent variations in scattering strength are carried out to provide a reference for the interpretation of phase data retrieved from experimentally acquired holograms. The iterative phase retrieval algorithm is then applied to protein data, indicating that both molecular density and charges can be related to features in the phase reconstructions, while the presence of metals does not correlate with specific phase signals at the current resolution obtainable from the experimental data.Since proteins are inherently three-dimensional, approaches towards three-dimensional reconstruction schemes are discussed, which will be the focus of future work.

EPFL2022

Characterization and prediction of peptide structures on inorganic surfaces

Dmitrii Maksimov

EPFL2022

Amplitude and phase reconstruction for Low-Energy Electron Holography of individual proteins

Hannah Julia Ochner

EPFL2022

Characterization and prediction of peptide structures on inorganic surfaces

Synthesis, characterization and conformational studies of switch-peptides

Amplitude and phase reconstruction for Low-Energy Electron Holography of individual proteins

Characterization and prediction of peptide structures on inorganic surfaces

Amplitude and phase reconstruction for Low-Energy Electron Holography of individual proteins

Synthesis, characterization and conformational studies of switch-peptides