Computational microbiology of bacteria: Advancements in molecular dynamics simulations.

Microbiology is traditionally considered within the context of wet laboratory methodologies. Computational techniques have a great potential to contribute to microbiology. Here, we describe our loose definition of "computational microbiology" and provide a short survey focused on molecular dynamics simulations of bacterial systems that fall within this definition. It is our contention that increased compositional complexity and realistic levels of molecular crowding within simulated systems are key for bridging the divide between experimental and computational microbiology.

Impact of PROTAC Linker Plasticity on the Solution Conformations and Dissociation of the Ternary Complex.

The conformational behavior of a small molecule free in solution is important to understand the free energy of binding to its target. This could be of special interest for proteolysis-targeting chimeras (PROTACs) due to their often flexible and lengthy linkers and the need to induce a ternary complex. Here, we report on the molecular dynamics (MD) simulations of two PROTACs, MZ1 and dBET6, revealing different linker conformational behaviors. The simulation of MZ1 in dimethyl sulfoxide (DMSO) agrees well with the nuclear magnetic resonance study, providing strong support for the relevance of our simulations. To further understand the role of linker plasticity in the formation of a ternary complex, the dissociation of the complex von Hippel-Lindau-MZ1-BRD4 is investigated in detail by steered simulations and is shown to follow a two-step pathway. Interestingly, both MZ1 and dBET6 display in water, a tendency toward an intramolecular lipophilic interaction between the two warheads. The hydrophobic contact of the two warheads would prevent them from binding to their respective proteins and might have an effect on the efficacy of induced cellular protein degradation. However, conformations featuring this hydrophobic contact of the two warheads are calculated to be marginally more favorable.

Polymyxin B1 within the E. coli cell envelope: insights from molecular dynamics simulations.

Polymyxins are used as last-resort antibiotics, where other treatments have been ineffectual due to antibiotic resistance. However, resistance to polymyxins has also been now reported, therefore it is instructive to characterise at the molecular level, the mechanisms of action of polymyxins. Here we review insights into these mechanisms from molecular dynamics simulations and discuss the utility of simulations as a complementary technique to  experimental methodologies.

Isolated Crohn's Disease of the Appendix Presenting as Acute Appendicitis in a 60-Year-Old South Asian Female: A Case Report, Review of Literature, and Follow-Up Recommendations.

The isolated appendiceal Crohn's disease without preceding bowel symptoms is a rare phenomenon, especially in older patients. In this case report, we present a 60-year-old female with isolated appendiceal Crohn's disease presenting with acute appendicitis. She presented with classical features of appendicitis with elevated inflammatory markers. She underwent an appendectomy which showed an excessively swollen, oedematous, and reddish appendix with swelling extending to the base of the caecum. Histological evaluation was suggestive of Crohn's disease, and subsequent colonoscopy was unremarkable. Following appendectomy, she was asymptomatic without any recurrence of disease. The atypical morphological appearance of the appendix should raise suspicion of Crohn's disease. This case highlights the importance of histopathological analysis of the specimen, especially in abnormal clinical findings. The prognosis of such patients seems to be good, and additional treatment is rarely needed.