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Why do some enzymes exhibit faster than diffusion kinetics?

Do molecular dynamics simulations exhibit DNA replication?

  • Even for a toy small DNA sample, if it's run through a molecular dynamics simulation with the appropriate enzymes and spare base pairs and helicase, does it show the DNA replication behavior?

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    Has it been done? : NO Can it be done in the near future? : I highly doubt it Can it be done in the distant future? : I would like to think so The biggest challenge in all MD simulations is the time/length scale issue. How big is your system? What is the time scale you want to study? are two very important questions. To study DNA replication with enzymes, DNA strands, water, ions,base pairs for few hundred microseconds, seems like a daunting task (even with DE Shaw computers, and oh, Blue Waters). Not to forget that DNA is a highly charged system and electrostatic calculations are not the quickest, and enzymes are HUGE molecules. Also, molecular simulations are only as accurate as your force field. You build your force field (there are a lot of good existing ones), so, if you want to study DNA replication, you have to make sure your force field has all the right ingredients (i.e. capture all the necessary interactions). Here are a few forcefield issues current researchers face: a) Representing divalent ions is very difficult using pairwise potentials, and we know how important it is to represent Mg/Mn/Zn etc. b) Need for polarizable force fields to better capture the nuances in DNA electrostatics, right now almost all of the available force fields use fixed charges c) DNA molecules are highly flexible and have a large conformational space, and the forcefield should be able to capture this flexibility d) Hydrogen bonding is core to replication, and this rules out coarse graining, there aren't many smart ways to coarse grain H-bonding.

Sai Janani Ganesan at Quora Visit the source

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I believe there are a number of issues. 1. The DNA molecule is friggin massive; current simulations (at least at university HPC level) can only do simple biological simulations like bilayer simulations, and single protein simulations, and even these have be coarse-grained rather than all- atomic. A molecule like DNA *will* have to be coarse-grained, which in itself is not good; A, T, C, G will pretty much be identical on a CG level, and adding specificity to each other does not have a 100% chance of making sure C goes with G and A going with T, meaning that there will be a huge mess. 2. Bulk properties. Its hard enough already with water divided into the numerous 'preferable' force fields (e.g. TIP3P) FF, and these FFs can be notoriously unreliable, especially in CG-MD simulations. (Random freezing, which needs to be heated up to get rid of, but in the process might ruin the entire enzyme and backbone chain) How does one configure a force field for bulk properties around the DNA and the enzymes involved to adequately support the myriad of organic species flying around? 3. Again size issues; the entire molecule + the DNA polymerase etc is extremely computationally expensive to simulate. However, if one 'splits' the DNA to parts to mimic 'some' kind of replication, it would be difficult to reproduce DNA in the end as the elastic properties of the phosphate chain is not adequately represented. And remember, this needs to be coarse-grained too. 4. On top of all of the above, there are *numerous* intermolecular forces involved; electrostatic, VdW, hydrogen.. again, these are *very* important to the entire process of replication, and CG detail, I believe, is simply not enough for this. 5. Finding the starting condition for the replication may be a difficult task itself. Most biological simulations I know and do are equilibrated in a NVT then let go to a NPT for example (typical for bilayers). An enzyme replication process, I would imagine, would take *numerous* trial and errors to get the right starting config. MCMC is completely out of the question as well.

Sang Young Noh

MD is based on newton's second law of motion (F=ma); it can only deal with classical mechanics. DNA replication involves formation/breaking of hydrogen bonds (which involve electrons). Electron are light and fast and therefore this makes us go into quantum mechanics. So no MD will not exhibit DNA replication!

Anonymous

No! This is extremely far away from feasible. The unsolved problem in a nutshell is we don't understand water. Water is an unfathomably complex dynamic chaotic system. See for details.

Allan Steinhardt

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