The evolution of multiple active site configurations in a designed enzyme

Developments in computational chemistry, bioinformatics, and laboratory evolution have facilitated the de novo design and catalytic optimization of enzymes. Besides creating useful catalysts, the generation and iterative improvement of designed enzymes can provide valuable insight into the interplay between the many phenomena that have been suggested to contribute to catalysis. In this work, we follow changes in conformational sampling, electrostatic preorganization, and quantum tunneling along the evolutionary trajectory of a designed Kemp eliminase. We observe that in the Kemp Eliminase KE07, instability of the designed active site leads to the emergence of two additional active site configurations. Evolutionary conformational selection then gradually stabilizes the most efficient configuration, leading to an improved enzyme. This work exemplifies the link between conformational plasticity and evolvability and demonstrates that residues remote from the active sites of enzymes play crucial roles in controlling and shaping the active site for efficient catalysis

Exploring human-guided strategies for reaction network exploration: Interactive molecular dynamics in virtual reality as a tool for citizen scientists

The emerging fields of citizen science and gamification reformulate scientific problems as games or puzzles to be solved. Through engaging the wider non-scientific community, significant breakthroughs may be made by analyzing citizen-gathered data. In parallel, recent advances in virtual reality (VR) technology are increasingly being used within a scientific context and the burgeoning field of interactive molecular dynamics in VR (iMD-VR) allows users to interact with dynamical chemistry simulations in real time. Here, we demonstrate the utility of iMD-VR as a medium for gamification of chemistry research tasks. An iMD-VR "game"was designed to encourage users to explore the reactivity of a particular chemical system, and a cohort of 18 participants was recruited to playtest this game as part of a user study. The reaction game encouraged users to experiment with making chemical reactions between a propyne molecule and an OH radical, and "molecular snapshots"from each game session were then compiled and used to map out reaction pathways. The reaction network generated by users was compared to existing literature networks demonstrating that users in VR capture almost all the important reaction pathways. Further comparisons between humans and an algorithmic method for guiding molecular dynamics show that through using citizen science to explore these kinds of chemical problems, new approaches and strategies start to emerge

QM/MM MD and Free Energy Simulations of G9a-Like Protein (GLP) and Its Mutants: Understanding the Factors that Determine the Product Specificity

Certain lysine residues on histone tails could be methylated by protein lysine methyltransferases (PKMTs) using S-adenosyl-L-methionine (AdoMet) as the methyl donor. Since the methylation states of the target lysines play a fundamental role in the regulation of chromatin structure and gene expression, it is important to study the property of PKMTs that allows a specific number of methyl groups (one, two or three) to be added (termed as product specificity). It has been shown that the product specificity of PKMTs may be controlled in part by the existence of specific residues at the active site. One of the best examples is a Phe/Tyr switch found in many PKMTs. Here quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed on wild type G9a-like protein (GLP) and its F1209Y and Y1124F mutants for understanding the energetic origin of the product specificity and the reasons for the change of product specificity as a result of single-residue mutations at the Phe/Tyr switch as well as other positions. The free energy barriers of the methyl transfer processes calculated from our simulations are consistent with experimental data, supporting the suggestion that the relative free energy barriers may determine, at least in part, the product specificity of PKMTs. The changes of the free energy barriers as a result of the mutations are also discussed based on the structural information obtained from the simulations. The results suggest that the space and active-site interactions around the ε-amino group of the target lysine available for methyl addition appear to among the key structural factors in controlling the product specificity and activity of PKMTs

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Measurements of Higgs boson production in the decay channel with a pair of ττ leptons in proton-proton collisions at s\sqrt{s} = 13 TeV

A preprint version of the article is available at arXiv:2204.12957v2 [hep-ex], https://arxiv.org/abs/2204.12957v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables, including additional supplementary figures and tables, can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-19-010 (CMS Public Pages). Report number: CMS-HIG-19-010, CERN-EP-2022-027.Measurements of Higgs boson production, where the Higgs boson decays into a pair of τ leptons, are presented, using a sample of proton-proton collisions collected with the CMS experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb^{−1}. Three analyses are presented. Two are targeting Higgs boson production via gluon fusion and vector boson fusion: a neural network based analysis and an analysis based on an event categorization optimized on the ratio of signal over background events. These are complemented by an analysis targeting vector boson associated Higgs boson production. Results are presented in the form of signal strengths relative to the standard model predictions and products of cross sections and branching fraction to τ leptons, in up to 16 different kinematic regions. For the simultaneous measurements of the neural network based analysis and the analysis targeting vector boson associated Higgs boson production signal strengths are found to be 0.82 ± 0.11 for inclusive Higgs boson production, 0.67 ± 0.19 (0.81 ± 0.17) for the production mainly via gluon fusion (vector boson fusion), and 1.79 ± 0.45 for vector boson associated Higgs boson production.SCOAP3

Energy-scaling behavior of intrinsic transverse-momentum parameters in Drell-Yan simulation

Data Availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use, and open access policy https://dx.doi.org/10.7483/OPENDATA.CMS.7347.JDWH .A preprint version of the article is available on arXiv, arXiv:2409.17770v2 [hep-ph] (https://arxiv.org/abs/2409.17770). [v2] Tue, 8 Apr 2025 23:23:48 UTC (450 KB). Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/GEN-22-001 (CMS Public Pages). Subjects: High Energy Physics - Phenomenology (hep-ph); High Energy Physics - Experiment (hep-ex). Report numbers: CMS-GEN-22-001, CERN-EP-2024-216An analysis is presented based on models of the intrinsic transverse momentum (intrinsic ) of partons in nucleons by studying the dilepton transverse momentum in Drell-Yan events. Using parameter tuning in event generators and existing data from fixed-target experiments and from hadron colliders, our investigation spans 3 orders of magnitude in center-of-mass energy and 2 orders of magnitude in dilepton invariant mass. The results show an energy-scaling behavior of the intrinsic parameters, independent of the dilepton invariant mass at a given center-of-mass energy.We congratulate our colleagues in the CERN accelerator departments for the excellent performance of the LHC and thank the technical and administrative staffs at CERN and at other CMS institutes for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centers and personnel of the Worldwide LHC Computing Grid and other centers for delivering so effectively the computing infrastructure essential to our analyses. Finally, we acknowledge the enduring support for the construction and operation of the LHC, the CMS detector, and the supporting computing infrastructure provided by the following funding agencies: SC (Armenia), BMBWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, FAPERGS, and FAPESP (Brazil); MES and BNSF (Bulgaria); CERN; CAS, MoST, and NSFC (China); MINCIENCIAS (Colombia); MSES and CSF (Croatia); RIF (Cyprus); SENESCYT (Ecuador); ERC PRG, RVTT3 and MoER TK202 (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); SRNSF (Georgia); BMBF, DFG, and HGF (Germany); GSRI (Greece); NKFIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); MES (Latvia); LMTLT (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MOS (Montenegro); MBIE (New Zealand); PAEC (Pakistan); MES and NSC (Poland); FCT (Portugal); MESTD (Serbia); MCIN/AEI and PCTI (Spain); MOSTR (Sri Lanka); Swiss Funding Agencies (Switzerland); MST (Taipei); MHESI and NSTDA (Thailand); TUBITAK and TENMAK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA)