text: Well, not everything. I had to learn to arrive at dinner parties a few minutes late. Arrive a few minutes early and the hosts, who may be missing key articles of clothing, look at you like you're a serial killer with leprosy who works for the IRS. Arrive exactly on time and they look at you like "Oh, you're one of those." So I now strive to arrive somewhere between three and five minutes after the appointed hour. This is often easy to pull off since I've been either driving around the block or parked at the corner for the previous eight to 10 minutes. On occasion, I will spot another guest doing the same thing. Sometimes, we smile and wave at each other, but usually I pretend to be having trouble finding the right house.
  So, arriving early is as bad as arriving late, but how late? That's a good question, and the answer varies by city, state, country and time of year, not to mention race and ethnicity. (Ever heard of Gaylight Savings Time?) But for our purposes here, I'm going to pull an Emily Post and announce ' as if I'm reading it off a stone tablet ' that one should ideally arrive at a dinner party within eight minutes of the appointed hour. Any later than that and you should phone the host with an estimated time of arrival. Why eight minutes? Because it isn't all the way to 10, and there's something about being 10 minutes late that smacks of carelessness, hence rudeness. Disagree, anyone out there? Well then let's hear from you. Pronto.
  
  Аннотация: NAD+-dependent formate dehydrogenases(FDH) catalyze the oxidation of formate to CO2 with reduction of NAD+ to NADH. Eukaryotic FDHs catalyze this reaction by the ordered kinetic mechanism, whereas bacterial enzymes act by the random mechanism. The substrate channel in bacterial FDHs may be responsible for the random mechanism. Thus, search for substitutions blocking the substrate channel is helpful for better understanding of kinetic mechanisms at the molecular level. On the basis of a structural analysis and multiple alignment of FDHs representative sequences, we suggested following substitutions in FDH structure from Pseudomonas sp. (PDB ID 2NAC): F311W, Y102F and double F311W Y102F. All modifications were performed using the program UCSF Chimera. We used GROMACS software for their characterization. The F311W modification has demonstrated the minimum radius of the substrate channel (0,7 A after 6 ns of MD simulation). The superposition of 2NAC structure and Y102F demonstrates that hydrophobic side chains around substrate channel came closer together (per ~0,4 A) in Y102F after 30 ns of MD simulation. Resulting hydrophobic cavity hampers the charged substrate migration to active center, as it becomes energetically unfavorable. The structural analysis of double mutant F311W Y102F shows that the substrate channel is sterically blocked. Molecular modeling reveals the modifications blocking substrate channel of FDH (F311W Y102F, F311W, Y102F) which may be useful in following experimental investigation of FDHs kinetic mechanism. All simulations were performed using the facilities of the Supercomputer Centers “Lomonosov”, “Chebushev” [Sadovnichy et al., 2013] and “Arian Kuzmin”.