Variational Methods for Biomolecular Modeling

Structure, function and dynamics of many biomolecular systems can be characterized by the energetic variational principle and the corresponding systems of partial differential equations (PDEs). This principle allows us to focus on the identification of essential energetic components, the optimal parametrization of energies, and the efficient computational implementation of energy variation or minimization. Given the fact that complex biomolecular systems are structurally non-uniform and their interactions occur through contact interfaces, their free energies are associated with various interfaces as well, such as solute-solvent interface, molecular binding interface, lipid domain interface, and membrane surfaces. This fact motivates the inclusion of interface geometry, particular its curvatures, to the parametrization of free energies. Applications of such interface geometry based energetic variational principles are illustrated through three concrete topics: the multiscale modeling of biomolecular electrostatics and solvation that includes the curvature energy of the molecular surface, the formation of microdomains on lipid membrane due to the geometric and molecular mechanics at the lipid interface, and the mean curvature driven protein localization on membrane surfaces. By further implicitly representing the interface using a phase field function over the entire domain, one can simulate the dynamics of the interface and the corresponding energy variation by evolving the phase field function, achieving significant reduction of the number of degrees of freedom and computational complexity. Strategies for improving the efficiency of computational implementations and for extending applications to coarse-graining or multiscale molecular simulations are outlined.Comment: 36 page

Electronic Structures of LNA Phosphorothioate Oligonucleotides

Important oligonucleotides in anti-sense research have been investigated in silico and experimentally. This involves quantum mechanical (QM) calculations and chromatography experiments on locked nucleic acid (LNA) phosphorothioate (PS) oligonucleotides. iso-potential electrostatic surfaces are essential in this study and have been calculated from the wave functions derived from the QM calculations that provide binding information and other properties of these molecules. The QM calculations give details of the electronic structures in terms of e.g., energy and bonding, which make them distinguish or differentiate between the individual PS diastereoisomers determined by the position of sulfur atoms. Rules are derived from the electronic calculations of these molecules and include the effects of the phosphorothioate chirality and formation of electrostatic potential surfaces. Physical and electrochemical descriptors of the PS oligonucleotides are compared to the experiments in which chiral states on these molecules can be distinguished. The calculations demonstrate that electronic structure, electrostatic potential, and topology are highly sensitive to single PS configuration changes and can give a lead to understanding the activity of the molecules. Keywords: LNA phosphorothioate, DNA/LNA oligonucleotide, diastereoisomers, Hartree-Fock calculations, iso-potential surface, anion chromatogram

Advanced Computer Graphics Aided Molecular Visualization and Manipulation Softwares: The Hierarchy of Research Methodologies

In the present day, the huge obstacles, and the major technical problems encountered by the teaching and research faculties, academicians, industrial specialists, laboratory demonstrators and instructors, fellow students and researchers, etc. are to adopt integrative approaches of demonstrating (learning) chemistry and chemical education, and the realistic ways of delivering (grasping) scientific materials articulately with graceful and effortless manner. Towards minimizing these challenges, various audio-visual tools and technologies, advanced computer aided molecular graphics, freely available electronic gadgets assisted chemistry and chemical education apps, human unreadable data reading and accessing softwares, etc. are being incorporated worldwide as the most indispensable physical and electronic means for successful professionalisms. This short article is essentially a collective report underscoring extraordinary approaches, incredible efforts, and innovative skills of the computer based chemical and molecular graphics towards illuminating intrinsic parts of the chemistry and chemical education, and revealing various aspects of the cutting -edge research. As their representatives, herein, the different type computer coding languages based graphical tools such as Molden, GaussView, Jmol, and Visual Molecular Dynamics (VMD) are referred, and elucidated their potential applications and remarkable attempts in the advancement of diverse areas of chemistry and chemical education. Beside this, the most essential graphical features, unique rendering abilities with magnificent views, splendid visualizing skills, awesome data accessing functionalities, etc. of each of them, and their invaluable roles for studying complex molecules, biomolecules, crystals, and the entire material assemblies as well as for investigating global and local molecular physicochemical properties are presented concisely with the special stresses on their relatively better and comparatively more applicable distinctive attributes explicitl

Modeling Electrostatics and Geometrical Quantities in Molecular Biophysics Using a Gaussian-Based Model of Atoms

Electrostatic and geometric factors are critical to modeling the interactions and solvation effects of biomolecules in the aqueous environments of biological cells as they respectively influence the polar and non-polar components of the associated free energies. Conventional protocols use a hard-sphere model of atoms to devise and study the underlying thermodynamics. But this traditional model tends to overlook some of the important biophysical aspects at the cost of oversimplification of the representation of the solute-solvent environments. Here an alternative and physically appealing model of atoms – a Gaussian-based model, is presented which replaces the hard-sphere model with a smooth density-based description of atoms. This dissertation explains the derivation of a physically appealing dielectric distribution from the Gaussian schematic to model the electrostatics of biomolecules using the implicit-solvent/Poisson-Boltzmann (PB) formalism. It also demonstrates the advantages of using it for computing geometric properties of a molecule such as its volume and surface area (SA) for estimating non-polar portions of the free energy. While highlighting the qualitative importance of the Gaussian-based model, it offers conceptual proofs towards its validity through computational investigations of explicit solvent simulations. It also reports the key features of the Gaussian-based model, which impart to it the capacity of accurately capturing the crucial biophysical factors that characterize biomolecular properties, namely – the effect of intrinsic conformational flexibility and salt distribution. The non-triviality of these factors and their portrayal through the Gaussian models are meticulously discussed. A major theme of this work is the implementation of the Gaussian model of dielectric distribution and volume/SA estimation into the PB solver package called Delphi. These developments illustrate the manner in which the utility of Delphi has been expanded and its reputation as a popular tool for modeling solvation effects with appreciable time-efficacy and accuracy has been enhanced

A theoretical study of metal-organic frameworks

Among the options for carbon sequestration, the development of CO2 capture materials has gained momentum over the past two decades. The design and construction of chemical and physical absorbents for the capture of CO2 and clean energy storage are a crucial technology for a sustainable low-carbon future. Metal-organic frameworks (MOFs) provide a new vision for the adsorption of molecules on solid surfaces. The interest in MOFs is owed to their ultrahigh porosity, high surface areas and tuneable pore sizes and shapes. The main objective of this thesis was to adopt a rational predictive capacity used in MOF design to control properties such as framework porosity and flexibility on a molecular scale. The in-silico studies were carried out by using ab initio quantum mechanical approaches such as density functional theory and perturbation theory. In addition, semi-classical methods like the Grand Canonical Monte Carlo (GCMC) approach was also used. A structural motif called vicinal fluorination was adopted to study MOF linkers in isolation and in a framework. An extensive conformational study, in various solvents, was carried out to investigate the effect of vicinal fluorination on the isolated MOF linkers and therefore elucidate their conformational stability. The effect of fluorination on adsorption isotherms was also investigated. Moreover, various fluorination patterns were explored. Adsorption isotherms of a non-fluorinated copperbased MOF based on experimental work, and its various fluorinated analogues were predicted using the GCMC method. It was found that vicinal fluorination is not dominant in controlling conformations of some MOF linkers. Rather, an interplay of interactions, including solute and steric interactions, influence the conformational stability on rotational profiles. However, vicinal fluorination was shown to control the flexibility of the linkers used in MOFs as it controls the force constants around the minima of rotational profiles of isolated MOF linkers. The study also highlighted the importance of the solvent on the relative energies of the linker conformations – this has a potential impact on the synthesis of MOFs. With the help of computational methods and validation from experimental data, the structural and sorption properties of the framework, upon fluorination, were shown to have consequences on the adsorption properties of the MOF. Vicinally fluorinated frameworks were shown to have higher uptakes at a low temperature and low pressures

C58 on Au(111): a scanning tunneling microscopy study

C58 fullerenes were adsorbed onto room temperature Au(111) surface by low-energy (~6 eV) cluster ion beam deposition under ultrahigh vacuum conditions. The topographic and electronic properties of the deposits were monitored by means of scanning tunnelling microscopy (STM at 4.2 K). Topographic images reveal that at low coverages fullerene cages are pinned by point dislocation defects on the herringbone reconstructed gold terraces (as well as by step edges). At intermediate coverages, pinned monomers, act as nucleation centres for the formation of oligomeric C58 chains and 2D islands. At the largest coverages studied, the surface becomes covered by 3D interlinked C58 cages. STM topographic images of pinned single adsorbates are essentially featureless. The corresponding local densities of states are consistent with strong cage-substrate interactions. Topographic images of [C58]n oligomers show a stripe-like intensity pattern oriented perpendicular to the axis connecting the cage centers. This striped pattern becomes even more pronounced in maps of the local density of states. As supported by density functional theory, DFT calculations, and also by analogous STM images previously obtained for C60 polymers (M. Nakaya et al., J. Nanosci. Nanotechnol. 11, 2829 (2011)), we conclude that these striped orbital patterns are a fingerprint of covalent intercage bonds. For thick C58 films we have derived a band gap of 1.2 eV from scanning tunnelling spectroscopy data, STS, confirming that the outermost C58 layer behaves as a wide band semiconductor