Integrative multiscale modeling and simulations of biomolecules with experimentally testable predictions

Includes bibliographical references.

PhD;2024:Molecular Biophysics Unit.

This thesis delves into four separate research works related to Integrative multiscale modeling and simulations of biomolecules. The first work deals with the puzzling case of the Pleckstrin Homology Domain (PHD), which is part of a full protein named Dynamin1(dyn1). The domain is known to play a "catalytic" role in the endocytic fission of the membrane. In other words, the rate of endocytic fission reduces drastically in the absence of PHD. We ask the question, how does dyn1-PHD act as a rate enhancer for a mechanical process such as fission? We used a reductionistic approach in designing biomolecular simulations that answer this posed question and provide molecular-level insights into its interaction with the membrane. This led to the discovery of a novel variable loop(VL) named VL4, following the previously discovered three variable loops. For the first time in the field of dynamin1, we presented a complete molecular-level understanding of all four variable loops and the nanoscopic interactions that go into the facile fission event triggered by dynamin1 using its pleckstrin homology domain. We proposed mutations in VL4 that will compromise the binding fidelity, which our experimentally verified. We further used an integrative approach of combining simulations with low-resolution cryo-EM data to tease out the distance of these loops in invitro assembled dynamin polymer on lipid membrane. In the second work, we address one of the biophysical aspects relevant to the theme of "Origin of Life". We explored the role of the heterogeneous diffusive nature of lipid bilayers in facilitating pre-polymer configurations of nucleotides, which might be a precursor to the formation of some of the early molecules of ribonucleic acids. Using atomistic simulations, we discovered that the lipid bilayers with both liquid-ordered and liquid-disordered phases facilitate enhanced membrane-nucleotide interaction, which in turn reduces the three-dimensional search space among the nucleotides to two-dimensional search on the lipid bilayer. The third project involved the development of a coarse-grained model of multidomain proteins capable of generating ensembles consistent with experimental scattering data. The last project involved the development of a high-resolution coarse-grained model of ribonucleic acid (RNA) molecules capable of capturing a wide variety of intra-molecular interactions found in nucleic acids