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MUD transcript:  20-01-00

Protein Geometry & Protein Synthesis

Course room(s): PPS 

23:00:44  ClareS connects.
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23:00:55  ClareS says "Hi"
23:01:03  ChristopherA says "hello"
23:01:07  ClareS says "sorry I was a couple of minutes late"
23:01:30  DavidM says "Hello, everybody"
23:01:38  ClareS says "we have had some quite serious computer problems today, so I'm really pleased that you've made it"
23:01:54  ClareS says "... has anyone had unusual problems connecting??"
23:01:56  MonikaS says "Hi to everyone!"
23:02:04  ChristopherA says "This is my first time finally got my internet link to work"
23:02:13  ClareS will wait a couple of minutes for latecomers before starting properly...
23:02:45  ClareS says (to christopher) "I'm very pleased that it's working now -- welcome to the MUD!"
23:03:42  MonikaS says "No, I haven't got any problems, so far."
23:03:52  ClareS says (to monika) "good..."
23:04:01  ChristopherA says (to ClareS) "Hope I get the hang of these commands quickly"
23:04:17  ClareS says (to christophera) "you're doing fine so far"
23:04:34  LesleyM connects.
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23:04:53  ClareS says "in yesterday's session we spent most of the time talking about section 3, protein geometry..."
23:05:02  ClareS says (to lesleym) "welcome!"
23:06:10  ClareS says "I'd really like to focus on section 3 and/or 4, but apart from that it's up to you..."
23:06:20  ClareS says "anyone like to start with a question?"
23:06:37  LesleyM says (to ClareS) "thank you. I am hoping to learn from other people's quaetions today"
23:07:34  ClareS looks round expectantly...
23:09:04  BartoszB connects.
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23:09:25  DavidM says "Does anybody have difficulties with torsion angles?"
23:09:38  ClareS says (to bartozsb) "welcome! -- we've really only just started"
23:10:38  BartoszB says "Hello everyone! Sorry for being late"
23:10:39  LesleyM says "I fell OK about the torsion angles - if not fluent about them."
23:10:58  ClareS says "yesterday we spent a long time discussing the definitions of torsion angles, which angles define them and how they are measured"
23:12:40  ClareS says "the difference between +60 and -60 degrees, etc..."
23:12:57  DavidM says "If we took the mirror image of a protein, does anybody know how the torsion angles would be affected?"
23:13:07  ClareS says "...and how they are recorded on the Ramachandran plot"
23:13:22  ClareS says (to davidm) "interesting question..."
23:13:47  LesleyM says "by "how they are measured" you mean clock wise etc, not physically, I take it?"
23:14:42  ClareS says (to lesleym) "yes, that's right... tho' how protein structure is measured (strictly, determined) physically is also a valid question"
23:15:16  ClareS says "you all realise that it's not possible to determine *exactly* the positions of the atoms, don't you?"
23:16:26  LesleyM says "yes - but how much is the average tolerance +/-"
23:17:02  ClareS says (to lesleym) "that depends on the resolution to which the structure is measured"
23:18:01  ClareS might need DavidM's help here -- he's a practical crystallographer and some of his research is concerned with the precision to which structures are measured
23:19:08  LesleyM says "is there also an intrinsic uncertainty deriving from the nature of the orbitals etc?"
23:20:05  DavidM says "It depends on the seolution of the crystal structure determination and the error will also be less in a main chain than at the end of a side chain"
23:20:17  ClareS says (to lesleym) "yes, naturally -- but this is swamped by the uncertainty derived from the precision of the instruments used"
23:20:39  DavidM says "Sorry, resolution, not seolution!"
23:20:59  ClareS says "the ends of the side chains move around more than the main chain"
23:21:23  ClareS says "have any of you (not DavidM!) used the term "temperature factor" to describe this?"
23:21:55  DavidM says "In the main chain the erro may be less than 5 degrees, at the end of a lysine side chain it might be indeterminate if the atoms are waving around in the solvent"
23:22:34  ClareS says "also, some whole residues are much more rigid than others"
23:23:02  ClareS says "residues in the central core and particularly near the activ site"
23:23:37  ClareS says "will be rigid, those in loops on the surface will be more flexible"
23:24:22  ClareS says "residues in secondary structures also tend to be rigid"
23:24:56  ClareS says "and the less flexible a residue is, the easier it is to determine accurately the positions of the residues"
23:25:03  ChristopherA says "is that why it is sometimes difficult to define certain amino acids from an electron density map?"
23:25:22  ClareS says (to christopher) "yes"
23:25:49  MichaelS connects.
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23:26:00  LesleyM says "if the residues are in fact so variable in their position in certain cases, how important are they to function these waving residues I mean>"
23:26:30  ClareS says (to michaels) "welcome!"
23:26:38  MichaelS says " Hello all. Sorry I'm late"
23:27:48  ClareS says (to lesleym) "not very... the fact that some residues are in flexible loops is a good indication that they are not critical for function"
23:27:56  ChristopherA says "All the residues in the protein contribute to the function in some why, don't they?"
23:28:40  ClareS says (to michaels) "we're discussing the precision of determining protein structures"
23:28:57  ClareS says (to christophera) "not really..."
23:29:20  DavidM says "Sometimes a mobile residue (eg Lys 41 in bovine ribonuclease) can be fixed in an active site when a substrate binds and then play an important role"
23:29:23  ClareS says (to christophera) "the technique of site directed mutagenesis is used to determine which residues are really important"
23:30:03  MichaelS says "thanks. I actually have had some contact wit hthis stuff. I think that in small proteins/peptides the role of the individual residues becomes more significant"
23:30:25  ClareS says "also if you look at an alignment of the sequences in a protein family you'll see that some positions are really well conserved and others seem to be random"
23:30:25  ChristopherA says (to ClareS) "Well even if they are only hydrogen bonding to the solvent they help to maintain the structural integraty of the protein"
23:30:47  ClareS says (to christophera) "that is true.. but in some cases it just doesn't seem to matter which amino acid is there"
23:31:24  ClareS says "e.g. in a surface loop where any polar or charged amino acid will be able to h-bond to the solvent as well as any other"
23:32:03  ClareS says "you will study sequence alignments in the next section... Bioinformatics"
23:32:43  ClareS says (to michaels) "that depends on the short protein or peptide..."
23:33:06  ClareS says "some short peptides in particular are extremely flexible"
23:33:08  MonikaS disconnects.
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23:33:25  ChristopherA says (to ClareS) "That depends how you look at it. At first sight thats how it looks but as other AA would be different in the sequence, that amino acid would become important."
23:33:44  ClareS says "others have real rigid structures, usually held together by e.g. metal ions or disulphide bonds"
23:35:50  ClareS says "sorry about that short break, I was kicked out of Netscape for some reason"
23:36:22  ClareS says (to christophera) "sorry... I'm not quite sure what you mean"
23:36:46  DavidM says "The most difficult residue to accommodate in a sequence can often be proline because its phi torsion angle is very constrained to ~-60"
23:36:54  ClareS says "are you talking about different sequences in a protein family, or about mutagenesis?"
23:37:33  ClareS says "it's more difficult to accommodate changes in the core of the protein, and less in the loops"
23:37:59  MichaelS says " k a very basic question, but is there any way we can look at comments that have been made ealier in the session, before we have joined?"
23:38:53  ClareS says "I'm not exactly sure whether you can look at the transcript during the session, sorry"
23:39:11  ClareS says "I will certainly post this session and yesterday's to the web site to-morrow"
23:39:21  ClareS says (to davidm) "do you know the answer to that?"
23:40:05  MichaelS shrugs shoulders, thanks ClareS
23:40:42  ClareS says (to michaels) "you can always send an email to the MUD wizard, IanTickle"
23:41:01  ClareS says "i.tickle@mail.cryst.bbk.ac.uk if you don't have his address to hand"
23:41:12  LesleyM says "a slight digression - is there any benefit to using Protein Explorer rather than Rasmol?"
23:41:30  ClareS says (to davidm) "that is, if our email is working again.. do you know if it is?"
23:42:31  ClareS says (to lesleym) "most of our demos are designed with Rasmol in mind as that's the most platform independent program"
23:43:01  ClareS says (to lesleym) "but Protein Explorer (which is an enhancement of Chime) should work"
23:44:08  ChristopherA says (to ClareS) "I try to re-explain: Nature will make what appears to be a random mutation so that it may still fit the sequence to the 3D structure, due to alterations in another portion of the sequence. Does that make any more sense?"
23:44:12  ClareS says "Protein Explorer has more features than Rasmol"
23:44:31  ClareS says (to christophera) "yes, that makes plenty of sense -- thanks!"
23:44:58  LesleyM says "yes, it seems to be an upgrade of Rasmol"
23:45:01  ClareS says "this is very true, and is why some families like the globins have very variable sequences"
23:45:32  ClareS says "a large hydrophobic residue will fit into a pocket made by a small one..."
23:45:53  ClareS says "... in another member of the family the small and large residues will be reversed"
23:46:18  ClareS says "if you mutate one residue without changing the others it interacts with the protein will not function well"
23:46:39  LesleyM says (to Clare) "you mentioned "temperature factor" earlier. How significant is that?"
23:46:41  ClareS says "but there will always be some residues on the surface of the protein that can more or less be changed at random"
23:46:58  ClareS says "does that make sense?"
23:47:11  MichaelS says " Sorry, Clare, but doesn't what Christopher is describing require either 2 different mutations, or else require the protein to be operating at reuced efficiency for a time, until the second, 'corrective' mutation occurs?"
23:48:21  BartoszB says "I have a small question - Does the sequence of in "less" important parts of protein(far from core and more flexible) affect the way that proteins folds? I don't Mean the result - I know I t's always the same, but following stages of this process ? ?"
23:48:39  ClareS says "yes, this would require 2 different mutations..but we're talking about proteins that diverged early in evolutionary history"
23:49:15  ClareS says "they had millions or billions of years for the "correct" mutations to occur together"
23:49:55  ClareS says (to bartozsb) "quite little is known about the exact mechanism of protein folding so far"
23:50:31  ClareS apologises to Bartosz for mis-spelling his name :)
23:51:09  ChristopherA says "Yes, but aren't those residue the optimum for the proteins native enviroment?"
23:51:20  ClareS says (to lesleym) "the temperature factor is a mathematical way of indicating how rigid an atom is"
23:51:35  MichaelS says " I've seen data presented where an individual residue has been changed to each of the remainder, and the effect is mostly detrimental. How can a protein generate any evolutionary advantage in this way?"
23:51:35  ClareS says (to lesleym) "the temperature factor is a mathematical way of indicating how rigid an atom is"
23:52:45  ClareS says (to lesleym) "a temperature factor is recorded for each atom in the PDB file"
23:53:24  ChristopherA says "The evolutionary advantage only becomes apparent in a different enviroment to its native one."
23:53:57  ClareS says "they are called "temperature factors" just by analogy: atoms with high "temperature factors" are those that move most"
23:54:02  MichaelS says " ue enough, but as long a t"
23:54:12  LesleyM says (to ClareS) "thank you - I knew I had seen it some where."
23:54:31  ClareS says "i.e. those at the end of long side chains, and those in the loops"
23:55:39  MichaelS says " Sorry about that, forgot the refresh delay. Chris, I was going to say that what you say is true enough, but as long as the environment remains reasonably constant, the mutated protein is still disadvantageous, no?"
23:56:10  ClareS says "if you look at a molecule in Rasmol (or Chime or the Protein Explorer ;) you will be able to colour by temperature factor"
23:56:52  ClareS says "by convention, rigid parts of the molecule are blue ("cold") and flexible parts are yellow or red ("hotter")"
23:57:08  ClareS says (to bartoszb) "there is a *wealth* of literature on protein folding"
23:57:22  ClareS says "and I don't really know where to start with recommendations"
23:57:28  ChristopherA says "Yes and therefore would be selected against, unless it displayed an unseen advantage,e.g. sickle cell against malaria"
23:58:44  MichaelS says " Touche."
23:59:15  LesleyM disconnects.
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23:59:24  ClareS says "you could start with the protein folding section of the latest volume of Current Opinion in Structural Biology"
23:59:42  ClareS says "unless David can recommend any good recent reviews?"
23:59:50  MichaelS says "to ChristopherA"
23:59:53  ClareS looks at David expectantly ;)
00:00:27  LesleyM connects.
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00:00:32  ChristopherA says "therefore for a mutation to stay it must go hand in hand with a change in enviroment, even though it might be incredibly slight"
00:01:09  ChristopherA says (to MichaelS) "Sorry can't type quick enough"
00:01:25  ClareS says "some mutations will be able to stay because they make very little difference"
00:01:29  BartoszB says "I suppose the data are derived from protein crystallography but how 'exactly' temperature factor i s calculated?"
00:01:39  ClareS says "but these are, admittedly, seldom crucial.."
00:01:53  ChristopherA says (to MichaelS) "Why Touche?"
00:02:11  ClareS will leave that one to David and another day.. or possibly the Protein Crystallography course??
00:02:12  BartoszB says (to ClareS) "Thank you"
00:02:34  DavidM says "I cannot give any references on protein folding immediately, but I will consult colleagues involved in this area and email what they say to the PPS list"
00:02:34  ClareS says "in any case, it's getting very late in the UK -- I'll be going to bed soon ;)"
00:03:03  ClareS says "of course you may carry on discussing protein evolution for as long as you like ;)"
00:03:10  DavidM says "Temperature factors are calculated from the diffraction pattern"
00:03:17  ClareS says "are there any final questions?"
00:03:44  DavidM says "The higher the temperature factors, the weaker the diffraction pattern"
00:03:47  MichaelS says (to Christopher) "That's why I'm running through Mavis Beacon!!! The touche was because I'd forgotten about things like sickle cell...a very good example;)"
00:04:08  ClareS says (to davidm) "if you want to start that explanation at this hour it's up to you, but you'll be here for a while"
00:04:13  LesleyM says "regarding the Synthesis section. This is quite extensive. Are there any particular points that need to be emphasized here?"
00:04:19  ClareS says (to michaels) "Mavis Beacon??"
00:04:35  ChristopherA says (to ClareS) "Just one, What format can we expect this assignment to be next week?"
00:05:03  ClareS says (to lesleym) "the emphasis of the course is on the structures.. you just need a broad overview"
00:05:20  ClareS says (to christophera) "two different types of assignment..."
00:05:29  ClareS says "short answer questions and quizzes"
00:05:34  MichaelS says (to ClareS) "It's a typing tutorial application. I have it for Mac, but I've also seen it for Wintel machines. It's very good so far!!"
00:06:01  ClareS says "the quizzes are multi-choice and on the web -- you get the answers immediately and we don't get to know what you answer"
00:06:22  ClareS says "you will be assigned to tutor groups soon (hopefully over the next couple of days)"
00:06:49  ClareS says "we would like you to email your answers to the short answer questions to your tutors by the end of the self-assessment fortnight"
00:06:56  ClareS says "is that OK??"
00:07:13  ClareS says (to michaels) "thanks, I think I'd find that useful too ;)"
00:07:36  ChristopherA says (to ClareS) "Yes Thanks."
00:08:08  ClareS yawns
00:08:42  LesleyM says "I will bid you all farewell and get to writing answer keys for my own students - a la prochaine"
00:08:46  ClareS looks round to see if there are any more final questions
00:09:02  ChristopherA says (to ClareS) "Looks like somebody needs their beauty sleep"
00:09:25  ClareS grins (tiredly)
00:09:44  DavidM waves
00:09:58  MichaelS says " Goodnight all. I hope any North Americans have a good evening, and those of us on the island can get some sleep!!;-)"
00:10:15  ClareS says "thank you all for making it such a lively discussion"
00:10:32  DavidM disconnects.
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00:10:35  ChristopherA says "Bye, Bye everybody"
00:10:49  ClareS waves goodnight
00:11:02  LesleyM disconnects.