4 research outputs found
Investigating substitutions in antibody–antigen complexes using molecular dynamics: a case study with broad-spectrum, Influenza A antibodies
In studying the binding of host antibodies to the surface antigens of pathogens, the structural and functional characterization of antibody–antigen complexes by X-ray crystallography and binding assay is important. However, the characterization requires experiments that are typically time consuming and expensive: thus, many antibody–antigen complexes are under-characterized. For vaccine development and disease surveillance, it is often vital to assess the impact of amino acid substitutions on antibody binding. For example, are there antibody substitutions capable of improving binding without a loss of breadth, or antigen substitutions that lead to antigenic escape? The questions cannot be answered reliably from sequence variation alone, exhaustive substitution assays are usually impractical, and alanine scans provide at best an incomplete identification of the critical residue–residue interactions. Here, we show that, given an initial structure of an antibody bound to an antigen, molecular dynamics simulations using the energy method molecular mechanics with Generalized Born surface area (MM/GBSA) can model the impact of single amino acid substitutions on antibody–antigen binding energy. We apply the technique to three broad-spectrum antibodies to influenza A hemagglutinin and examine both previously characterized and novel variant strains observed in the human population that may give rise to antigenic escape. We find that in some cases the impact of a substitution is local, while in others it causes a reorientation of the antibody with wide-ranging impact on residue–residue interactions: this explains, in part, why the change in chemical properties of a residue can be, on its own, a poor predictor of overall change in binding energy. Our estimates are in good agreement with experimental results—indeed, they approximate the degree of agreement between different experimental techniques. Simulations were performed on commodity computer hardware; hence, this approach has the potential to be widely adopted by those undertaking infectious disease research. Novel aspects of this research include the application of MM/GBSA to investigate binding between broadly binding antibodies and a viral glycoprotein; the development of an approach for visualizing substrate–ligand interactions; and the use of experimental assay data to rescale our predictions, allowing us to make inferences about absolute, as well as relative, changes in binding energy
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Simulation Aspects of the Mechanics of Biomolecular Filaments: Crackling in DNA unzipping and the Contraction of Bacteriophage Tails
Both DNA and the contractile tail sheaths of bacteriophages are examples of biofilaments, whose monomer subunits consist of nucleotides and proteins respectively. The bending and torsional deformations of tail sheaths and strand separation of ds-DNA are important phenomena essential for their biological functions. Despite the great prevalence and biomedical importance of contractile delivery systems, many fundamental details of their injection machinery and dynamics are still unknown. On a similar note, a detailed theoretical understanding of the monomer-level dynamics of DNA unzipping under constant force is also lacking in literature. In the subsequent chapters of this thesis, I will describe how computer simulations can be used to perform an in-depth study of both of the above phenomena. I would begin by describing a method which uses molecular dynamics simuations to calculate the bending and torsional stiffness constants of two biologically relevant contractile tail sheaths: bacteriophage T4 and R2-pyocin. Next, I would describe how the stiffness constants can be incorporated in a continuum dynamic model to simulate the dynamics of contractile nano-injection machineries. Finally, I would describe how MD simuations can be used to study the unzipping dynamics of a long DNA homopolymer, which would to a fascinating discovery where the 'avalanches' in the unzipping velocity time series show a power law variation in avalanche size and time similar to crackling noise in other unrelated physical systems. The studies of these phenomena are of great biological significance; studying contractile tail injection dynamics can open up new avenues in potential bio-nanotechnological applications like experimental phage therapy, and understanding of DNA unzipping at the monomer level is relevant to many essential genetic processes like replication, transcription, recombination, DNA repair, and -in biotechnology- to DNA sequencing
Multiscale modeling of macromolecular biosystems
In this article, we review the recent progress in multiresolution modeling of structure and dynamics of protein, RNA and their complexes. Many approaches using both physics-based and knowledge-based potentials have been developed at multiple granularities to model both protein and RNA. Coarse graining can be achieved not only in the length, but also in the time domain using discrete time and discrete state kinetic network models. Models with different resolutions can be combined either in a sequential or parallel fashion. Similarly, the modeling of assemblies is also often achieved using multiple granularities. The progress shows that a multiresolution approach has considerable potential to continue extending the length and time scales of macromolecular modeling