This is what I presumed.

Honglai,

We are interested in mechanics of biomolecules in general but more focused on simulations (instead of modeling in this jClub article). Specifically, we are looking at mechanosensitive channels at this moment and developing multiscale simulation protocols. This will be one of our main directions in the coming years. Of course, just like you, we are also and equally interested in materials for energy, nanomechanics, thin films, nanoindentation, and solid-fluid interactions. I am updating my department webpage and should post some new information soon.

Xi,
So, how far do you plan to go in biomechanics? Any particular research directions?

Well I think that you have a very good point there and I also often think that science has a problem with scales. We look at something small and want to understand the bigger picture. Sometimes it is fruitful but often it leads to "wrong" conclusions. But there is really no alternative way to do science because if we dont understand the basics we can not understand the advanced......

Michelle, you are absolutely right, processes in cell can take a longer time. I referred to mechanotransduction (which is more mechanics-related and closely related with protein channels discussed in the jClub) to illustrate that, even a ms (or even μs) process is too difficult to be followed by all-atom simulations. Like you said, length and time scale challenges present in almost every material mechanics problems, not just biomechanics.

Time scales for physiological processes in cells can take more than ms, and in many cases much closer to s. There's then yet another huge leap towards thinking about biology and disease -- in humans we have to try and understand how processes taking place in cells on second-type time scales relate to diseases that appear in years. A similar problem exists in length-scales: a cell is tens of microns; a person is (usually!) several meters in size.

I applaud the advances in biomechanics at molecular length- and time-scales but hope that these advances are kept in the perspective of the larger picture. To actually use our understanding of molecular process to affect healthcare there's a large leap in scale, and this leap is not irrelevant in considering healthcare as at least one good reason for studying biomechanics (aside from basic understanding of the universe and the meaning of life, of course!)

I think that the ultimate test for dynamical processes in biomolecules is simulation of the folding process going from a random coil state to a native (folded) state. Several papers have shown that through MD simulations one can simulate the folding of small peptides with less than about 30 amino acids. But since most enzymes is typically much larger and that the folding process in general on the time scale of ms compared to only ns for large systems in MD we still have a long way to go.

Since typical processes occuring in the cell, such as mechanotransduction, can take several ms, all-atom simulations are simply impossible without some biased tricks.

Thanks for the information.

I can understand now that all-atom simulations of the conformational changes of proteins can be prohibitively expensive.

While most coarse-grained models of proteins can give reliable information about directionality of motion (such as structural transition), but not about the magnitude of motion. It's usually straightforward to correlate known structural transitions to a set of normal modes (which are collective basis vectors). It's much more difficult to predict structural transitions based on a single structure; e.g., what happens after an ATPase binds ATP. In other words, the work that you mentioned is quite nice but not yet predictive. For more quantitative coarse-graining attempts, you may want to refer to Greg Voth's work.

Hi, Chen. I am very thankful to your reply to my comments. You said that coarse-graining of proteins is still at infant stage and there are still many unsolved problems. As far as I guess, the coarse-graining of proteins is attributed to the fact that the native topology (represented by contact map - map indicates the native contact) plays a role in protein dynamics. That is, in general, the stiffness matrix for proteins based on native contacts becomes sparse matrix that leads to possibility of coarse-graining. I think that that is why further model reduction from Tirion's coarse-grained model is possible.

I have simple question for you: You said that "there are many unsolved problems". Can you give some example on your comment? To my best knowledge, the challenging problem is to understand protein dynamics and/or mechanics for large protein complexes that I am still working on. Especially, I am working on protein dynamics of large protein complex (e.g. GroEL-GroES) by using various model reduction methods. Also, I am working on coarse-grained model for mechanics of protein crystals.

Anyway, I would like to hear from you about some examples of unsolved problems in coarse-graining of proteins, and your opinion for further directions on protein modelings. Thank you again for your reply.

Honglai,

The actual number varies a lot because the cell size can be very different. On average a protein can contain millions of molecules, and a cell can easily contain over billions of molecules. See here for a rough estimation.

Xi,

how many atoms in a cell? Counted in molecules, what is the number?

Thank you Honglai. All components discussed here must be embedded within a cell and its surrounding environment and thus it is usually assumed the system temperature is a constant. In MD simulation that would be to put the entire system in a "water bath" with a constant temperature. The thermal fluctuation can, of course, influence the system equilibrium and dynamics (especially those from the solvent molecules). This is discussed in Mahadevan and Schulten's work.

Since the journal club could only include 3-5 papers for discussion, I only chose the most representative (and more pioneering) papers in this area (based on my humble and limited knowledge). I am aware of the three NMA/ENM papers you mentioned, which are more or less follow-ups on this topic. The papers you listed will be important for the readers to further understand the topic.

For coarse graining of proteins though, I feel it is more computational than analytical; plus, comparing with coarse graining of lipid, the coarse graining of protein is still at its infant stage and there are still many unsolved problems. Moreover our group is also doing research in this area. Overall I leave this topic out of this issue of journal club but I welcome discussion on this topic; or you may consider to include that in the theme of a future issue of journal club.

Probably, it may be good to include Bahar's paper on protein modeling. First, we may consider her paper published in J. Mol. Biol. in 2003: Xu, C., Tobi, D., and Bahar, I., J. Mol. Biol., 333, 153-168 (2003). In her work, it was shown that conformation transition from T form (tense conformation: ligand-unbound state) to R form (relaxed conformation: ligand-bound state) was induced by purely elastic forces (entropic forces). That is, the conformational transitions are related to low-frequency normal modes responsible for entropic forces (thermal fluctuations). For understanding conformational transition by using NMA, one may also consider the following papers:

Zheng, W., Brooks, B.R., Biophys. J., 88, 3109-3117 (2005)
Ikeguchi, M., Ueno, J., Sato, M., Kidera, A., Phys. Rev. Lett., 078102 (2005)

Moreover, in recent year, there was an issue on further coarse-graining on protein structures. In Bahar's recent work, it was shown that collective motion of large proteins can be represented by small number of degrees of freedom. Specifically, in her work, the structure (~10^4 residues) of GroEL-GroES complex can be represented by only 30 nodal points. For details, you may refer to her paper: Chennubbhotla, C., and Bahar, I., Lecture Notes in Computer Science, 3909, 379-393 (2006). Further, I also provided a method of coarse-graining of protein structures. For details, you may look at the paper: Eom, K., Baek, S.-C., Ahn, J.-H., Na, S., J. Comput. Chem., in press, doi: 10.1002/jcc.20672.

Dear Xi,

I finished reading the papers you suggested. Thanks for providing very good references for this interesting topic. I would like to say something, although I know nothing about biomechanics.

How to analyze the temperature effects for DNA, RNA and proteins? How was the temperature of DNA, RNA, or proteins, calculated in the previous molecular dynamics analyses?

As discussed before (//m.limpotrade.com//m.limpotrade.com/node/1064), temperature, as well as other thermodynamic concepts such as entropy and the 2nd law of thermodynamics, will become confusing at the molecular scale.

The challenge is that, the temperature fluctuation will affect greatly the functioning of DNA, RNA, and proteins. It is a very important issue that we just cannot ignore.