Posters, Online Workshop, April 23-24, 2021 “COMPUTER SIMULATION AND THEORY OF MACROMOLECULES” Poster – #163 Probing the Interaction of Protamine with Zn-Insulin through Biophysical and Molecular Docking Studies Presenting author: Soumya Aggarwal Jawaharlal Nehru University, School of Physical Sciences, New Delhi, India Co-author(s): Manoj Munde Interaction of insulin with a small cationic peptide called protamine is of particular interest because of its pharmacological relevance in the case of severe diabetes. The action profile of insulin-protamine formulation is from crystallizing insulin with zinc in the presence of basic poly-arginine peptide protamine [1]. Zinc plays important role in the biosynthesis and storage of insulin as insulin structure is strongly modulated by the binding of zinc ions. Zinc ions inhibit the fibrillation of monomeric insulin at physiological pH values by forming a soluble Zn-insulin complex [2]. In spite of the long history and successful use of insulin-protamine formulation, the binding mechanism of the insulin-protamine complex is not known. In our work, we are using various biophysical techniques such as Circular Dichroism, Intrinsic fluorescence, ITC, and molecular docking studies to analyze binding protamine-insulin binding. [1] M. Norrman, F. Hubalek & G. Schluckebier (2007). Structural characterization of insulin NPH formulations. European Journal of Pharmaceutical Sciences.30, 414-423. [2] M. F. Dunn (2005). Zinc-ligand interactions modulate assembly and stability of the insulin hexamer – a review. Biometals.18, 295-303. Poster, Online Workshop, April 23-24, 2021 “COMPUTER SIMULATION AND THEORY OF MACROMOLECULES” Poster – #633 Fast and Accurate Constant pH Molecular Dynamics in GROMACS Presenting author: Noora Aho University of Jyväskylä, Nanoscience Center, Department of Chemistry, Computational Biomolecular Chemistry Group, Jyväskylä, Finland Co-author(s): Pavel Buslaev, Gerrit Groenhof, Berk Hess pH is one of the key parameters affecting the function and dynamics of proteins and other biomolecules. The protonation states of titratable groups in a biomolecule can change at different pH, which alters the electrostatic interactions of the molecule. Still, being able to dynamically change the protonation states and altering the pH is not a standard option in most of the classical computer simulation software. Usually in simulations, protonation states for titratable groups are initially chosen at the given pH by selecting the statistically most probable protonation. This prevents the examination of pH-dependent phenomena, which is why an efficient constant pH molecular dynamics (MD) method in explicit solvent is highly desired. The previous version of continous λ-dynamics based constant pH MD for GROMACS was released for version 3.3.3. The dynamics of the λ-particles was calculated by linearly interpolating between the Hamiltonians of all possible protonation states [1]. In our current implementation, λ-dynamics relies on the interpolation of the charges of the atoms in titratable groups, instead of interpolating the Hamiltonians. This results in a huge improvement in speed compared to the previous version, as the charge interpolation approach only requires calculating once the electrostatic potential for the system with interpolated charges. Thus, even for N titratable sites only one PME call is needed, instead of the previously required 2N PME calls. Together with the improvement in running speed, we will present a convenient scheme to describe titratable groups with more than two protonation states, such as histidine. Currently, we are performing final tests and working on the parallelization scheme. In collaboration with the Gromacs development team, we are integrating our implementation into the main branch of the code with the aim of making it available in future GROMACS releases. [1] S. Donnini, F. Tegeler, G. Groenhof, H. Grubmüller, Journal of Chemical Theory and Computation., 7, 1962-1978 (2011). Poster, Online Workshop, April 23-24, 2021 “COMPUTER SIMULATION AND THEORY OF MACROMOLECULES” Poster – #658 In silico and in vitro Analysis of a Novel Bis Coumarin Derivative Induced Anti Melanoma Effects: Suppression of the Phosphorylation of Epidermal Growth Factor Receptor (EGFR) and Proto-Oncogene Cellular Sarcoma (c-SRC) Related Downstream Pathways Presenting author: Quratul Ain Hamdard University, Department of Pharmaceutical Chemistry, Karachi, Pakistan & Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Hamdard University & Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi & Department of Dermatology and Allergic Disease, Ulm University, Germany Co-author(s): Abhijit Basu, M. Iqbal Choudhary, Karin Scharffetter-Kochanek Drugs with a high potency and selectivity toward multiple biological targets represent a novel and efficient drug discovery paradigm. Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. In clinical trials, highly selective or specific blocking of only one of the kinases involved in these signaling pathways has been associated with limited or sporadic responses. Improved understanding of the complexity of signal transduction processes and their roles in cancer has suggested that simultaneous inhibition of several key kinases at the level of receptors and/or downstream serine/threonine kinases may help to optimize the overall therapeutic benefit associated with molecularly targeted anticancer agents. Immunotherapy with CTLA-4 and PD-1 antibodies has emerged as recent breakthrough in the therapy of metastatic melanoma. However limited response rate, severe life-threatening or fatal side effects and resistant nature of malignant melanoma further fuels the urgent quest for new strategies in the battle against metastatic melanoma. A newly emerging concept for the treatment of advanced malignant melanoma is based on developing new synthetic compounds targeting multiple signaling pathways and their corresponding genes. We have discovered a novel multi targeted molecule belonging to the class of bis-coumarin, as a potential anti-melanoma and anti-metastatic drug candidate and have suggested it for further preclinical and clinical trials based on its ability of selectively killing melanoma cells and inhibiting their migration via targeting multiple phosphokinases. Poster, Online Workshop, April 23-24, 2021 “COMPUTER SIMULATION AND THEORY OF MACROMOLECULES” Poster – #209 The Full Model of the pMHC-TCR-CD3 Complex: A Structural and Kinetics Characterization Presenting author: Josephine Alba University of Fribourg, Department of Biology, Molecular Biophysics of Cellular Membranes Group, Fribourg, Switzerland & University of Rome "Sapienza" – Department of Chemistry Co-author(s): Marco D'Abramo, Oreste Acuto The machinery involved in cytotoxic T-cell activation requires three main characters such as: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3-complex which is a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied both in experimental and computational models, giving a contribution in understanding the complexity of the TCR triggering process. Nevertheless, a detailed study of the structural and dynamical characterization of the full complex (pMHC:TCR:CD3-complex) is still missing, due to insufficient data available on the CD3-chains arrangement around the TCR. The recent determination of the TCR:CD3-complex structure by means of Cryo-EM technique has given a chance to build the entire proteins system essential in the activation of T-cell, and thus in the adaptive immune response. Here, we present the first full model of the pMHC interacting with the TCR:CD3-complex, built in a lipid environment. To describe the conformational behaviour associated with the unbound and the bound states, all atoms Molecular Dynamics simulations were performed for the TCR:CD3-complex and for two pMHC:TCR:CD3-complex systems, bound to two different peptides. Our data point out that a conformational change affecting the TCR Constant β (Cβ) region occurs after the binding to the pMHC, revealing a key role of such a region in the propagation of the signal. Moreover, we found that the TCR reduces the flexibility of the MHC I binding groove, confirming our previous results. Poster, Online Workshop, April 23-24, 2021 “COMPUTER SIMULATION AND THEORY OF MACROMOLECULES” Poster – #498 Multiscale Simulations of Radical Cation Guanine in the Nucleosomal DNA Presenting author: Laleh Allahkaram ENS de Lyon, Chemistry Laboratory, Theoretical Chemistry Group, Lyon, France & ENS de Lyon Co-author(s): Elise Dumont, Natacha Gillet, Laleh Allahkaram All eukaryotic cells deal with the issue of tightly packing their genomes inside a small nucleus. This physical problem has been solved by the formation the chromatin1. Eukaryotic DNA is organized into nucleosome which is the fundamental unit of chromatin and comprises 147 base pairs of DNA wrapped around an octameric core composed of four pairs of histone proteins (2 pairs of H3-H4 and two pairs of H2A, H2B)2,3. Histone protein cores have very flexible protuberant tails which play a pivotal and critical role in regulating many biological processes such as transcription, expression, and DNA