@4406cuda I have the exact same problem as you, with exactly the same amp models (classic Fender + Marshall). This was immensely annoying for me, since I tried for weeks to fix this. I think I have roughly identified the problem recently. Let me describe it below.
I noticed the problem is not present at all with my Gibson SG, but with my Ibanez JS2410 the sound of the A string is horrible. So I sampled the raw input of the A string on both guitars and did a frequency spectrum analysis. If you have a look at the attached diagram, you can see that the Ibanez has a lot more pronounced overtones in the range of 2.5 kHz. I investigated this, and my impression is that the reason is a combination of the acoustic sound of the guitar with the position of the neck pickup, which seems to make this frequency range very prominent. (I tried to move a similar pickup to different positions on the neck and noticed that the chosen positioning is kind of "worst case" amplifying the frequencies around 2.5 kHz, while at other positions the problem disappears.)
When I use a parametric EQ block before the amp block and use a peaking filter with -10 dB and Q around 3.5 at 2.4 kHz, the sound becomes OK. Of course, this is kind of a strong change in a frequency range that is very important for the overall sound, and I wished I could have achieved this with lesser tweaking, but that is the best I was able to achieve. As mentioned, with my Gibson SG I don't have to do anything here, the sound is very good without any EQ-ing.
So I somehow had a first impression of what causes the problem, namely pronounced overtones of the guitar. To further investigate this, I had a look at the influence of the bright switch and bright cap value for the Fender and Marshall amp models. From what I know, the early Marshalls like JTM 45 I like to use are very similar to Fender amps of that time. This might be an explanation for why the problem appears with these models.
By switching off power amp modeling, I was able to see that the problem actually appears before the power amp stage. The annoying frequencies are created in the input/preamp stage with turned on bright switch and bright cap values above a certain threshold. So I tried to figure out what the influence of the bright cap is here. To this end, I placed a synthesizer block before the amp block, with a relatively low output level of something like -20 dB, according to the somehow lower levels of the annoying frequencies in the raw guitar signal, compared to the base frequencies. Then I tried different frequencies for a sine wave in the synth block and had a look at the shown output level in the grid overview, with bright switch off and on. I had the impression that for the amp models we are discussing, activated bright switch raises the frequencies we are talking about by a really large amount, which in case of my Ibanez seems to raise these frequencies to a level at which they become really annoying.
As a comparison, I tried my very old Line 6 POD 2.0 and it shows a similar behavior for the Ibanez, so I think the observed behavior is somehow "the truth", but I don't have access to a real tube amp to check this.
So to summarize, I think the problem might be caused by using a guitar model with pronounced overtones in the frequency range we are talking about, and that we are observing a somehow accurate amp/cab modeling here, i.e., what we get is simply how the guitar + (simulated or not) amp sounds like.
However, I hope that I am wrong with this, since I would like to get a good sound without using such a strong EQ-ing of my raw guitar signal. Turning off the bright switch is also not a really nice solution, since I found it is not trivial for me to EQ the signal by other means (parametric/graphical EQ) to get the desired overdriven sound with correct amount of "bite".
So I would appreciate any hints which could help me to improve things here, or also falsifying or supporting my observations a lot! Intuitively, I think it is somehow strange if there are some guitar models which sound very nice and some which sound totally crappy und unusable for these simple amps like classic Fender and Marshalls!
