Browsing by Author "Meuwly, Markus"

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    CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed
    (American Chemical Society, 2024) Hwang, Wonmuk; Austin, Steven L.; Blondel, Arnaud; Boittier, Eric D.; Boresch, Stefan; Buck, Matthias; Buckner, Joshua; Caflisch, Amedeo; Chang, Hao-Ting; Cheng, Xi; Choi, Yeol Kyo; Chu, Jhih-Wei; Crowley, Michael F.; Cui, Qiang; Damjanovic, Ana; Deng, Yuqing; Devereux, Mike; Ding, Xinqiang; Feig, Michael F.; Gao, Jiali; Glowacki, David R.; Gonzales, James E., II; Hamaneh, Mehdi Bagerhi; Harder, Edward D.; Hayes, Ryan L.; Huang, Jing; Huang, Yandong; Hudson, Phillip S.; Im, Wonpil; Islam, Shahidul M.; Jiang, Wei; Jones, Michael R.; Käser, Silvan; Kearns, Fiona L.; Kern, Nathan R.; Klauda, Jeffery B.; Lazaridis, Themis; Lee, Jinhyuk; Lemkul, Justin A.; Liu, Xiaorong; Luo, Yun; MacKerell, Alexander D., Jr.; Major, Dan T.; Meuwly, Markus; Nam, Kwangho; Nilsson, Lennart; Ovchinnikov, Victor; Paci, Emanuele; Park, Soohyung; Pastor, Richard W.; Pittman, Amanda R.; Post, Carol Beth; Prasad, Samarjeet; Pu, Jingzhi; Qi, Yifei; Rathinavelan, Thenmalarchelvi; Roe, Daniel R.; Roux, Benoit; Rowley, Christopher N.; Shen, Jana; Simmonett, Andrew C.; Sodt, Alexander J.; Töpfer, Kai; Upadhyay, Meenu; van der Vaart, Arjan; Vazquez-Salazar, Luis Itza; Venable, Richard M.; Warrensford, Luke C.; Woodcock, H. Lee; Wu, Yujin; Brooks, Charles L., III; Brooks, Bernard R.; Karplus, Martin; Chemistry and Chemical Biology, School of Science
    Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.
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    Stabilization of a protein by a single halogen‐based aromatic amplifier
    (Wiley, 2025) El Hage, Krystel; Dhayalan, Balamurugan; Chen, Yen-Shan; Phillips, Nelson B.; Whittaker, Jonathan; Carr, Kelley; Whittaker, Linda; Phillips, Manijeh H.; Ismail-Beigi, Faramarz; Meuwly, Markus; Weiss, Michael A.; Biochemistry and Molecular Biology, School of Medicine
    The utility of halogenation in protein design is investigated by a combination of quantitative atomistic simulations and experiment. Application to insulin is of complementary basic and translational interest. In a singly halogenated aromatic ring, regiospecific inductive effects were predicted to modulate multiple surrounding electrostatic (weakly polar) interactions, thereby amplifying changes in thermodynamic stability. In accordance with the simulations, we demonstrated stabilization of insulin by single halogen atoms at the ortho position of an invariant phenylalanine (2-F-PheB24, 2-Cl-PheB24, and 2-Br-PheB24; ΔΔGu = -0.5 to -1.0 kcal/mol) located at the edge of a protein crevice; corresponding meta and para substitutions had negligible effects. Although receptor-binding affinities were generally decreased (in accordance with packing of the native Phe at the hormone-receptor interface), the ortho-analogs retained biological activity in mammalian cells and in a rat model of diabetes mellitus. Further, the ortho-modified analogs exhibited enhanced resistance to fibrillation above room temperature in two distinct assays of physical stability. Regiospecific halo-aromatic stabilization may thus augment the shelf life of pharmaceutical insulin formulations under real-world conditions. This approach, extending principles of medicinal chemistry, promises to apply to a broad range of therapeutic proteins and vaccines whose biophysical stabilization would enhance accessibility in the developing world.