No book reference unfortunately, but this is what I learned back in the day from Gert Vriend and Geerten Vuister. Or at least what I took away from it and what I now teach myself:
The most important energie comes from the entropy of water. Water gaines freedom by not having to sit against hydrophobic parts of the folded protein. Hydrogen bonds do not really help for folding because an unfolded protein actually makes better hydrogen bonds than a folded one. So arguably hydrogen bonds are only damage control in the folded state. Side note: this is why checking for buried, unsatisfied hydrogen bond donors/acceptors is a good tool in model validation and protein engineering. Also good to note is that the backbone oxygen only makes one H-bond in helices/strands but can make two in the unfolded state.
There is a lot of flexibility loss (entropy) upon folding so you have to take that into account when considering the folded state versus the unfolded state. To stabilise a protein you can work on minimising that loss. So another trick I learned is that, if you can get away with that in the structure, any gly -> ala mutation is stabilising. Mutation ala-> pro works the same way. In that same logic, a hydrophobic residu on the surface is not really a problem for folding/stability per se. You lose nothing with respect to the unfolded state.
So if you take anything away from this. Do not consider just the folded state but always reason from the contrast between the folded and unfolded state.
HTH,
Robbie
On 14 Aug 2025 06:33, Natesh Ramanathan <[email protected]> wrote:
Dear All,I have read in old books and taught by able teacher while I was a student that :1. The most important non covalent interaction for protein stability is Van der Waals interaction.2. The most important non covalent interaction for protein folding is hydrophobic interaction.Does anyone recollect which book mentions this.. or any reference to the papers would be really helpful?While the points 1. and 2. may deviate for specific cases.. in general for most cases, these were valid, from my knowledge.Today.. Google says no.... for both these points 1 and 2...For both google says the most important ones are : hydrogen bond, hydrophobic interactions a and ionic interactions...Is it time to calibrate our old knowledge or disregard what google/AI says?Many thanks for your input..You can send me a private reply if you wish not to spam others INBOX.Need to set this right.. as it was bothering me and I need to teach with the right knowledge.Many thanks...Best regards,--
Natesh----------------------------------------------------------
"Live Simply and do Serious Things .. "
- Dorothy Mary Crowfoot Hodgkin OM, FRS
"In Science truth always wins"
- Max Ferdinand Perutz OM FRS
----------------------------------------------------------
Dr. Ramanathan Natesh
Associate Professor,School of Biology and Center for High-Performance Computing (CHPC),Founding and Current President of Cryo Electron Microscopy and 3 Dimensional Image Processing Society of India (CEM3DIPSI),Indian Institute of Science Education and Research Thiruvananthapuram (IISER-TVM),Maruthamala P.O., Vithura,Thiruvananthapuram, 695551, Kerala, India
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