Human vs. bacteria evolution (was: Simple refutation of neo-Darwinism)
zOz
> = Mike Syvanen in http://www.deja.com/=dnc/getdoc.xp?AN=701117117
||| = Wolfgang G. in http://www.deja.com/=dnc/getdoc.xp?AN=699930598
||| If I understand correctly then the experimental facts are the
||| following:
|||
||| 1) the first nalidixic acid resistant bacterium (mutant-1)
||| appears when a population reaches around 10^6 cells (by
||| mutation 1)
||| 2) the first streptomycin resistant (mutant-2) bacterium
||| appears when a population reaches around 10^9 cells (by
||| mutation 2)
||| 3) the first doubly resistent bacterium (mutant-1-2) appears
||| when a population reaches around 10^12 cells.
|||
||| Nevertheless you claim that these experimental facts are
||| consistent with the following assumptions:
|||
||| 4) both mutations are under the conditions of the experiment
||| entirely neutral
|||
||| 5) mutations 1 and 2 are completely independent of each other
|||
||| You consider the obvious contradiction between 1,2,3 and 4,5
||| as an "apparent dilemma [which] can be explained by the same
||| process that gives rise to the Luria-Delbruck fluctuation
||| phenomena".
|||
||| Nevertheless, if we can exclude a selection effect then simple
||| logic leads to the conclusion that (at least) one of the
||| following statements must be true:
|||
||| 5a) the rate of mutation 1 in mutant-2 is around 10^-3
||| (instead of 10^-6)
||| 5b) the rate of mutation 2 in mutant-1 is around 10^-6
||| (instead of 10^-9)
||| 5c) the rate of a combined mutation in the original form
||| is around 10^-12 (instead of 10^-15)
|||
||| All three possibilites refute your assumption 5.
> This problem does not have an exact or closed form solution;
> it yields a unwieldy combinatoric if you try. Let's consider
> 100 independent clones each of which will be grown to a final
> population of 10^12 cells. The mutation frequency to nalR is
> 10^-6 per cell division and the f to stpR is 10-9 per cell
> division. In 50 % of the cultures, the first mutation to nalR
> will appear when the population reaches 10^6, this mutant will
> grow with the culture and after 20 generations will contribute
> 10^6 offspring to the final culture. New mutations arising
> elsewhere will also contribute to the final. Thus when the
> population reaches 10^12 there will be 2 x 10^7 nalR mutants.
> In that last generation when 2x10^7 cells divide there will
> 10^-9 times 2 x 10^7 = .02 or 1 % of the original cultures will
> have nalR stpR mutants created by this pathway. In one percent
> of the cultures the first nalR mutant will arise when the culture
> reaches 10^4, this culture will result in a jackpot of nalR
> mutants. There is a 2% chance that the first nalR mutant arises
> at 2 x 10^4 cell, and 4% chance that the first appears at 4 x 10^4
> and so on. This second 50 % of the culture will have a slightly
> higher chance of producing nalR stpR doubles ( about 2%).
>
> So there is ca a 3 % chance of the double mutants arising such that
> nalR is produced first and stpR is produced second. The chances of
> the double being formed by stpR first and nalR second is also about
> 3%. Thus we would expect to find 6 cultures out of the 100, with
> double mutants.
>
> So to conclude when we calculate the odds by multiplying 10^-9 to
> 10^-6 to obtain 10^-15 we are calculating the odds that the
> double mutant will arise in the same cell and the same generation.
>
> Population geneticists have recognized this problem for many
> years that is why they deal in terms of frequency of alleles
> in populations and make no effort to relate that to mutation
> frequency.
I've learned a lot a when trying to understand these
paragraphs, namely about the relation between mutation rate
and rate of mutants. Nevertheless what I've learned is not
consistent with your statement that mutation frequencies
"are usually a little less than the frequency of mutants
that would be found in a typical population".
Let us define a "mutation rate per replication cycle" of
10^-6 in such a way that both bacteria emerging by cell
division from a sensitive one have each a chance of 10^-6
of being resistent.
If we start with 10^12 sensitive bacteria we get 2 x 10^12
bacteria by every replication cycle. Let us keep the number
of bacteria constant at 10^12 by randomly destroying
bacteria after every replication cycle. Then we get this
result:
No mutants by definition in cycle-zero, 10^6 mutants in
cycle-1, 2x10^6 mutants in cycle-2, 3x10^6 mutants in
cycle-3, 10^7 mutants in cycle-10, 10^8 mutants in
cycle-100 and so on. Already after 100 replication cycles
we get a "frequency of mutants" (i.e. 10^-4) which is
substantially higher than the "frequency of mutation"
(i.e. 10^-6).
What are the implications for our above "experimental
facts"?
1) the first nalidixic acid resistant bacterium (mutant-1)
appears when a population reaches around 10^6 cells (by
mutation-1)
We need 20 replication cycles in order to reach 10^6 cells
because 2^20 = 1.1 * 10^6. If the mutation rate were 10^-6
then we would expect on average not 1 but 20 resistent
bacteria when the population reaches 10^6 cells. So the
mutation rate must be only 10^-6 / 20 = 5 x 10^-8.
2) the first streptomycin resistant (mutant-2) bacterium
appears when a population reaches around 10^9 cells (by
mutation 2)
Because 30 cycles are necessary in order to reach 10^9 cells
the mutation rate must be 10^-9 / 30 = 3 x 10^-11.
In this way it becomes even more obvious that there is a
HUGE "contradiction between 1,2,3 and 4,5". Nevertheless my
conclusions concerning 5a,5b,5c represent rather a case
of naive than of simple logic.
Cheers, Wolfgang
Simple refutation of neo-Darwinism (Upright gait):
http://www.deja.com/=dnc/getdoc.xp?AN=698302471
http://www.deja.com/=dnc/getdoc.xp?AN=699138347
Sent via Deja.com http://www.deja.com/
Before you buy.
Howard Hershey
Actually, if the mean mutation frequency is 10^-6 per cell per
generation, when you reach a population size of 10^6, you would expect
the % of cultures with 0,1,2,3, or more *independent* resistant
mutants having occurred *prior to that time* to follow a Poisson
distribution. That means that for a mean of 1 mutant/generation/10^6
cells, 36.8% of the cultures should have no mutant, 36.8% should have
had 1 independent mutant, 18.4% should have two independent mutants,
and the rest would be distributed among cultures with 3 or more
independent mutations having occurred *at some point* prior to the
time of the measurement. Because the population is undergoing
exponential growth, the *fraction* of a particular cell population
that will be nal resistant is more dependent upon *when* the first
independent mutation occurs during exponential growth from a single
cell. That is, each *independent* mutation can give rise to a large
number of progeny with that particular mutation. Those progeny are
not independent mutations. At each generation, the probability of a
mutation is 10^-6. In a doubling population with parental survival,
there are about 20 generations until 10^6 cells exist, with each
generation having twice as many cells as the previous. The
probability of the mutation occurring in a cell in the first
generation is 10^-6, but the *cumulative* probability of the first
mutant (in the 63.2% of cultures in which one or mutations will occur)
having occurred by the 10th generation is about two in a thousand (the
probability of the first mutation in the 10th generation, with its
1000 cells, itself is aproximately 10^3*10^-6, and has the largest
single probability). The effect of such a jackpot (an early mutation)
is not to increase the number of *independent* mutational events, but
to produce a *lineage* of mutants that can make up a large fraction of
the cells in the culture. In a culture where such an event occurred,
one would expect about 1000 progeny of that single mutation to be
present at the time the culture had reached 10^6 cells, not one, even
if no other independent nal muation occurred. Thus there is a higher
percentage of nal resistant cells in such a culture (10^3/10^6) than
there would be of the percentage of *independent* mutational events (1/10^6).
As you increase the population size you look through to find the
mutants, the more the distribution of *independent* mutants in
different populations will resemble a bell curve closely centered on
mean mutation frequency, in this case 1 mutant per 10^6 cells. After
you reach the point where you no longer have any cultures without
mutants and essentially all populations have mutants (reached pretty
much by even 3 x 10^6, when only 5% of cultures lack a mutant), the
mean *percentage* of mutants will stabilize, since it is the time
point at which the *first* mutant exists that essentially fixes the
percentage of these mutants in that population.
Thus, in a population of 10^12 cells, one would expect, on average,
10^6 nal resistant cells +/- a standard deviation *by independent
mutation event*. There can be a somewhat to significantly higher
percentage of *all* nal resistant cells in specific cultures due to
those cases where there was early mutation (to reflect the skew due to
the timing of the first mutation). That is, looking over cultures,
the curve of mean percentage of nal resistant cells/culture is skewed
to the higher side. There will also be, on average, 10^3 strep
resistant cells in 10^12 cells. The *average* probability of
*independent* double mutants where the nal mutation occurred first is
the same as the probability of a strep mutation in a growing
population of cells that had reached 10^6 cells initially starting
from a single nal resistant cell. The total number of *independent*
double mutants would be twice that (since you need to add in the cases
where strep occurred first). There would, however, be considerable
*variance* in the number of nal resistant (and/or strep resistant)
cells in individual cultures. Specifically, because there is a skew
to higher percentage of mutation (rather than independent mutation) in
cultures because of the effect of the timing of the *first* mutant.
In lab, we do a selection for lacZ mutations (which grow and are white
under our conditions of selection). GalK and galT mutations also
grow, but are blue in cells which initially were non-mutants grown
from a single colony. The ratio of blue to white can vary by a factor
of 100, despite the fact that both types of mutants give an average
mutation frequency.
The probability of independent mutation to nalidixic acid resistance
is the same in every single generation from first to last. The only
thing that happens as you approach 10^6 cells is to apply that
probability to a larger number of cells making it more likely that the
first mutation in the population will occur within a few generations
of 10^6 cells. Absolutely nothing prevents it from occurring in the
very first generation.
Syvanen
> >
> > > This problem does not have an exact or closed form solution;
> > > it yields a unwieldy combinatoric if you try. Let's consider
> > > 100 independent clones each of which will be grown to a final
> > > population of 10^12 cells. The mutation frequency to nalR is
> > > 10^-6 per cell division and the f to stpR is 10-9 per cell
> > > division. In 50 % of the cultures, the first mutation to nalR
> > > will appear when the population reaches 10^6,
>
> Actually, if the mean mutation frequency is 10^-6 per cell per
> generation, when you reach a population size of 10^6, you would expect
> the % of cultures with 0,1,2,3, or more *independent* resistant
> mutants having occurred *prior to that time* to follow a Poisson
> distribution.
That is true. My scenario is an oversimplification, but it
doesn't change the final estimate by much.
[snip a reasonably accurate discussion of fluctuation until we
get to:]
>
> As you increase the population size you look through to find the
> mutants, the more the distribution of *independent* mutants in
> different populations will resemble a bell curve closely centered on
> mean mutation frequency, in this case 1 mutant per 10^6 cells. After
> you reach the point where you no longer have any cultures without
> mutants and essentially all populations have mutants (reached pretty
> much by even 3 x 10^6, when only 5% of cultures lack a mutant), the
> mean *percentage* of mutants will stabilize, since it is the time
> point at which the *first* mutant exists that essentially fixes the
> percentage of these mutants in that population.
Howard, you surprise me. The statement "mutants in
> different populations will resemble a bell curve closely centered on
> mean mutation frequency, in this case 1 mutant per 10^6 cells."
is flat out incorrect.
Let's go over this again. You agree that in the 100 cultures
when the cell number reaches 10^6 that 63 of them will have at
least one mutant cell. For simplicity let us focus on a culture
with one (the others will have more than one so we are estimating
a lower number with this approximation.) When the culture grows to
10^12 cells that one mutant will become 10^6 cells. When the
culture goes from 10^6 to 2 x 10^6 cells, we expect two more
independent mutants to arise (of course, as you pointed out,
the expectation here is Poisson distributed so this two is not
exactly correct, but close). These two mutants will also contribute
10^6 offspring to the final culture. When the culture goes from
2 x 10^6 to 4 x 10^6 cells, we expect 4 new mutants to arise and the
offspring from these 4 will contribute 10^6 cells to the final
culture. This occurs for each of the 20 generations between 10^6
and 10^12 cells so the number of mutants in the final culture will
be (20 x 10^6) or 2 X 10^7.
So your statement:
> Thus, in a population of 10^12 cells, one would expect, on average,
> 10^6 nal resistant cells +/- a standard deviation *by independent
> mutation event*.
cannot be correct if we expect at least 20 times that number
in 66% percent of the cultures.
Mike Syvanen
[snip remainder]
zOz
http://www.virusmyth.com/aids/data/drinhibit.htm
' The vogue explanation for the failure of the inhibitors to
' benefit AIDS patients is that HIV replicates so fast that it
' eventually develops mutant forms of protease that resist the
' inhibitors.
' The mutation theory is preposterous, but not just because its
' premise - that HIV replicates hyperactively - is false. The
' mutation theory is preposterous because it is illogical.
' Enzyme inhibitors work only because they are shaped like the
' substrates the enzymes act upon: when an inhibitor fits snugly
' into an enzyme's active site, then the substrate cannot. This
' is how inhibitors keep an enzyme from performing its task,
' which in this case is to produce HIV. Imagine one of these
' resistant, lab-created HIV proteases. It resists inhibitors
' because its active site is shaped in such a way that
' inhibitors cannot fit inside. That's great. But how in the
' world is the substrate going to fit? Remember, the inhibitor
' and the substrate have the same shape; they appear identical
' to the active site, the way a lock cannot tell the difference
' between a key and a copy of a key.
'
' Yet a representative from Vertex presented a poster showing
' that some of these lab-created mutants did indeed retain most
' of their ability to act upon particular substrates. But could
' such a mutant still produce virus?
'
' I reminded him that in order for an HIV protease to produce
' a new virus, it had to cleave eight different substrates,
' and pointed out that the ability to cut just one of those
' substrates did not represent the overall ability of the
' enzyme to produce HIV.
At least in the meanwhile the existence of protease-inhibitor
resistent HIV seems to be an experimental fact. Nevertheless
within a neo-Darwinian framework, Rasnick's argument makes
sense.
Isn't it an unexplainable miracle (within pure materialism)
that the HIV protease is able not only to recognize the
*EIGHT* different locations on the HIV super-protein but
also to cut the super-protein? In order to cut, the protease
must move and (allosterically) change its own form. Also
animals and humans have to move their bodies in order to
work.
Within a pannaturalistic framework (based on both the
material and psychic aspects of nature), even the fact
that proteases learn to distinguish between inhibitors
and substrate is not astonishing.
Wolfgang Gottfried G.
Pannaturalistic* evolution:
http://members.lol.li/twostone/E/psychon.html
*The term "naturalism" has unfortunately been
usurped by the materialistic ideology
zOz
|| = Wolfgang G. in http://www.deja.com/=dnc/getdoc.xp?AN=702960682
[ Quote from David Rasnick: ]
|| ' Enzyme inhibitors work only because they are shaped like the
|| ' substrates the enzymes act upon: when an inhibitor fits snugly
|| ' into an enzyme's active site, then the substrate cannot. This
|| ' is how inhibitors keep an enzyme from performing its task,
|| ' which in this case is to produce HIV. Imagine one of these
|| ' resistant, lab-created HIV proteases. It resists inhibitors
|| ' because its active site is shaped in such a way that
|| ' inhibitors cannot fit inside. That's great. But how in the
|| ' world is the substrate going to fit? Remember, the inhibitor
|| ' and the substrate have the same shape; they appear identical
|| ' to the active site, the way a lock cannot tell the difference
|| ' between a key and a copy of a key.
|
| No so: what is described here is only one possible form of
| inhibition-competitive inhibiton.
| There are other forms of inhibition, which have the inhibitor
| bind outside the enzymes active site (non-competititve
| inhibition): this form of inhibition is virtually irreversible
| since the inhibitors bond is covalent and not via weaker van
| der waals-forces as it would be the case with the reversible
| competitive inhibition. The advantage in using incompetitive
| inhibitors to disable viral or bacterial enzymes is obvious:
| the enzyme stays disabled and has to be replaced by the
| microorganism Of course the disadvantage is, that the enzyme-
| coding dna may mutate, changing parts of its structure which
| - of course - are outside the enzymes actual active site,
| thus keeping the enzymes function while no longer allowing
| incompetitive inhibition by a certain inhibitor.
Does this mean that the HIV protease has in addition to
EIGHT active sites (for eight substrates where the protease
cuts the HIV superprotein) at least one 'sensitive' site
which can be targeted by "non-competetive inhibitors"?
Cheers, Wolfgang
____________________________________________________________
BTW, the evolution debate is relevant to HIV/AIDS debate
because the assumption that HIV is a new killer virus is
very unlikely outside the reductionist premises of the
prevailing evolution theories. (That a microbe which can
be found in some regions in 30% or more of healthy adult
animals or humans cannot be a killer microbe should be
obvious).
"The Demographic Saturation Theory" is a logical consequence
of pannatualistic evolution. Here an extract:
http://members.lol.li/twostone/E/demography.html
The saturation thesis is relevant not only to humans but
to all organisms. It can hardly be denied that many animal
populations remain rather constant in size without
Malthusian struggles for survival. There are also limits
on animal breeding and plant cultivation.
There is even a saturation for pathogens like bacteria and
viruses. A pathogen of a local epidemic cannot be a threat
to mankind, nor can genetically engineered pathogens.
New methods to fight pests become possible: On the one
hand the pests are fought where they are harmful, and on
the other hand they are bred to saturation in places where
they don't do any harm.
Evolution of HIV & Half-life time of antibodies:
http://www.deja.com/=dnc/getdoc.xp?AN=687227462
Nick Bennett
On 11 Dec 2000, zOz wrote:
>
> Does this mean that the HIV protease has in addition to
> EIGHT active sites (for eight substrates where the protease
> cuts the HIV superprotein) at least one 'sensitive' site
> which can be targeted by "non-competetive inhibitors"?
I have a feeling that if you were to look at the target sites where HIV
cuts the polypeptides, they'd all be very similar... One active site for
8 "different" targets.
Non-competitive inhibitors don't necessarily have to target different
sites, if for example they irreversibly bind to the active site itself (ie
they're not competing for the normal substrate in an equilibrium, because
there will be no equilibrium...)
As a small point I think HIV pro is a serine protease, meaning it cuts
after serine residues (with other surrounding amino acids providing the
sequence specificity). I may well be mistaken here, but the same
principle applies if it's an aspartate protease etc etc.
Bennett
mcoo...@my-deja.com
100...@orange.csi.cam.ac.uk>,
HIV PRO is an aspartyl protease.
> Bennett
Len Pattenden
Wolfgang;
Protease inhibitors DO NOT mimic substrates. Have a look at the structure
of them, VX-478 has a Benzyl-sulfonic-amine moiety. It's not even an amino
acid (as substrates are). The state of catalysis is determined by the
isostere type. For example the hydroxyl-ethyl-amine try to mimic the high
energy *transition state* and because their shape is similar (at the point
of cleavage) to the transition state, they out compete substrates as they
are preordered to bind in the high energy state. Rasnick is well aware of
this and so his statement is a simplified child-like statement for those
sheep who read virusmyth.
HIV-1 PR is an aspartyl protease (does not form covalent attachments) and
it's active site "conforms" to different shaped substrates. The rate of
cleavage is determined by the sequence of the substrate, but also the
sequence of the active site binding pocket.
When inhibitors to HIV-1 PR were designed from the crystal structures,
they looked at maximum potency by hitting as many H-bonds as possible, so
the drugs are very large inside the active site, extending several
angstroms further into the substrate binding pockets. In this respect
there is no way they resemble substrates, and so a subtle change of say an
alanine to a valine can cause a loss of potency of an inhibitor by several
orders of magnitude without appreciably affecting the rate for a
substrate. Hence resistance with continued virion formation.
Once again your basic lack of fundamentals makes you look very silly.
Len...
David Canzi
zOz <wissensch...@my-deja.com> wrote:
>Extract from an article (Aug. 1996) by David Rasnick:
>http://www.virusmyth.com/aids/data/drinhibit.htm
> ' substrates the enzymes act upon: when an inhibitor fits snugly
> ' into an enzyme's active site, then the substrate cannot. This
> ' is how inhibitors keep an enzyme from performing its task,
> ' which in this case is to produce HIV. Imagine one of these
> ' resistant, lab-created HIV proteases. It resists inhibitors
> ' because its active site is shaped in such a way that
> ' inhibitors cannot fit inside. That's great. But how in the
> ' world is the substrate going to fit? Remember, the inhibitor
> ' and the substrate have the same shape; they appear identical
> ' to the active site, the way a lock cannot tell the difference
> ' between a key and a copy of a key.
If two molecules fit together perfectly, they would just stick
together, and neither molecule would change its shape. In order for a
protease to cut a protein, the process of binding must deform the
protein molecule. Afterwards, the molecules must be bound loosely
enough to allow them to separate. The fit between the molecules must
be imperfect for the protease to do its job.
A good inhibitor would be shaped to fit the protease's active site
*better*, and bind tighter, than the protein the protease normally
operates on.
(A number of years ago, I was puzzled as to how a molecule binding to
the outside part of a cell-surface receptor can have an effect inside
the cell. I eventually decided that the shapes of the sites that bind
are not perfectly matched, so that the molecules are deformed in the
process of binding, and the drawings in science magazines depicting
molecules fitting together like jigsaw pieces are misleading. I
realized while I read Rasnick's argument that similar conclusions apply
to the actions of proteases. I don't know if I'm actually right, I
just enjoyed the puzzle.)
--
David Canzi
Nick Bennett
On 11 Dec 2000 mcoo...@my-deja.com wrote:
>
> HIV PRO is an aspartyl protease.
>
Thx - live and learn ;-)
Did you have to quote the entire article though :-p
Bennett
zOz
> = Len Pattenden
>> = Wolfgang G. in http://www.deja.com/=dnc/getdoc.xp?AN=703594379
>> Does this mean that the HIV protease has in addition to
>> EIGHT active sites (for eight substrates where the protease
>> cuts the HIV superprotein) at least one 'sensitive' site
>> which can be targeted by "non-competetive inhibitors"?
> Protease inhibitors DO NOT mimic substrates. Have a look at the
> structure of them, VX-478 has a Benzyl-sulfonic-amine moiety.
> It's not even an amino acid (as substrates are). The state of
> catalysis is determined by the isostere type. For example the
> hydroxyl-ethyl-amine try to mimic the high energy *transition
> state* and because their shape is similar (at the point of
> cleavage) to the transition state, they out compete substrates
> as they are preordered to bind in the high energy state. Rasnick
> is well aware of this and so his statement is a simplified
> child-like statement for those sheep who read virusmyth.
I already play with the terrible idea that David Rasnick (the
former president of "The Group for the Scientific Reappraisal
of the HIV-AIDS Hypothesis") himself could be a central traitor
infiltrated by the AIDS establishment in order to undermine the
inpact of the dissidents, especially Duesberg's.
In http://www.deja.com/=dnc/getdoc.xp?AN=645237713 I wrote:
"Yuri [Kuchinsky] regularly quotes David Rasnick in his
postings. I'm not sure whether his intention is primarily to
create in his readers negative associations with David Rasnick,
a researcher I appreciate very much for his clear logical
reasoning."
"If persons, having seen several Yuri postings, will find
something with the name David Rasnick, then they won't take it
seriously because they (unconsciously) will associate Rasnick
with Yuri."
Because David Rasnick has even co-authored papers with Duesberg,
such negative associations will also fall on Duesberg (the only
AIDS dissident I'm sure I can trust in every respect).
Rasnick does not only openly acknowledge that he breaks rules
(see postscript of http://www.virusmyth.com/aids/data/drconf.htm)
but also regularly discredits himself by committing unnecessary
errors and by attacking AIDS researchers in a rather disgusting
way.
> HIV-1 PR is an aspartyl protease (does not form covalent
> attachments) and it's active site "conforms" to different
> shaped substrates. The rate of cleavage is determined by the
> sequence of the substrate, but also the sequence of the active
> site binding pocket.
>
> When inhibitors to HIV-1 PR were designed from the crystal
> structures, they looked at maximum potency by hitting as many
> H-bonds as possible, so the drugs are very large inside the
> active site, extending several angstroms further into the
> substrate binding pockets. In this respect there is no way they
> resemble substrates, and so a subtle change of say an alanine to
> a valine can cause a loss of potency of an inhibitor by several
> orders of magnitude without appreciably affecting the rate for
> a substrate. Hence resistance with continued virion formation.
>
> Once again your basic lack of fundamentals makes you look very
> silly.
Len, you're right inasfar as I'm too silly to understand why my
above rhetorical question makes me look silly.
Nevertheless it seems to me that YOU don't understand the
fundamentals we are dealing with in this thread.
It is generally acknowledged that enzyme-substrate interactions
are essentially based on the lock-and-key principle. That one
and the same key (i.e. active site) works for eight different
locks (i.e. substrates) makes the lock-and-key explanation
rather dubious, don't you think?
From a probabilistic point of view, it should be obvious to
every well-informed person that the complex bahaviour of the
HIV protease cannot be explained solely by physical and chemical
laws.
I discussed such issues in March 1999. Here some extracts:
It is necessary to have a concrete imagination of the
proportions between cells, enzymes, molecules and so on.
Therefore I have introduced the enlarged model where 1 mm
corresponds to 1 nm. The 'diameters' of enzymes are then
in the order of a few millimetres and the 'diameter' of a
water molecule is about 0.3 mm (there is room for 33.3
water molecules in 1 cubic millimetre).
Many enzymes work at defined places in a cell. If we create
an enlarged model, where enzymes are like little balls [of
a few millimeters], then the volume of the whole cell is
about 1000 cubic metres. Imagine concretely this situation:
a little ball must come very near to a substrat and the
substrat recognition even depends on the correct alignment
of the little ball. In addition to that, enzymes often have
to pass cell membranes in order to reach their destination.
What is the moving force of enzymes? It cannot be
electromagnetic attraction or repulsion. So the moving force
must primarily depend on random thermal motions (as Brownian
movements do).
Please imagine very concretely the many water molecules
(0.3 millimeters) colliding with the enzyme (e.g. a diameter
of some millimeters).
Cheers, Wolfgang
Relevant extracts from my posts on evolution of March 1999:
http://members.lol.li/twostone/E/deja6.html
Len Pattenden
On 13 Dec 2000, zOz wrote:
> I already play with the terrible idea that David Rasnick (the
> former president of "The Group for the Scientific Reappraisal
> of the HIV-AIDS Hypothesis") himself could be a central traitor
> infiltrated by the AIDS establishment in order to undermine the
> inpact of the dissidents, especially Duesberg's.
Not being a person to normally jump to the defense of the dissidents
(especially Rasnick whom I have a personal dislike of), I can assure you
he believes what he says. I have found him to be honest to what he sees,
but blinded to the literature supporting HIV causes AIDS. He has followed
Duesberg very literally ie *ALL* retroviri are harmless. I have
corresponded with him via e-mail, but he is no Duesberg. His shortcomings
shouldn't prejudice you against him so.
> Len, you're right inasfar as I'm too silly to understand why my
> above rhetorical question makes me look silly.
I'm sorry, this is usernet, if you wanted no response to your mutation
theory of HIV rubbish post, then you should have recited it to a mirror
and basked in your own intellect. Now you look down-right stupid.
> Nevertheless it seems to me that YOU don't understand the
> fundamentals we are dealing with in this thread.
Oh really?
> It is generally acknowledged that enzyme-substrate interactions
> are essentially based on the lock-and-key principle. That one
> and the same key (i.e. active site) works for eight different
> locks (i.e. substrates) makes the lock-and-key explanation
> rather dubious, don't you think?
See here you again show your lack of understanding of fundamental biology.
You keep trying to define something's behaviour as concrete when it can be
very fluid. The lock-and-key fit is only one theory, a competing theory is
the induced fit - that the enzyme and substrate changes it's shape to
conform. The Lock-and-key fit works for some enzyme types, as too does the
induced fit. Now don't you think that the induced fit theory would better
sit with HIV-1 PR?
I agree that most enzymes work on Brownian motion to "find" their
substrates. There are exceptions, but they will still exhibit such motion.
Pepsin for example is so charged on the outside that there is a nett
electrostatic attraction. In the case of HIV-1 PR it is expressed in a
poly-protein. The enzyme is literally attached to it's substrates and is
active inside a budding virion. The area it works in in more crowded than
a cell.
Len...