Dedicated stategies for GPCR MD simulation
As the most important membrane protein, GPCR MD simulation is a quite hot topic nowadays. However, how to assemble protein/membrane system and which forcefield to assign for the whole system are two main critical and tough task for GPCR simulations.
1. Assemble protein/membrane system
Many tools are now available for protein/membrane building including:
VMD (http://www.ks.uiuc.edu/Research/vmd/)
CHARMM-GUI (http://www.charmm-gui.org/)
Desmond System Builder (http://www.deshawresearch.com/resources_desmond.html)
g_membed (http://wwwuser.gwdg.de/~ggroenh/membed.html)
InflateGro (http://moose.bio.ucalgary.ca/index.php?page=Translate_lipdis)
VMD can support well for POPC and POPE membrane system building with CHARMM27 and CHARMM36 FF. However, one have to add additional solvent and ions into the system by tcl script from VMD tutorial. It will also need some script to merge membrane and protein. Moreover, since the lipids are not pre-equilirated, it would be necessary to equilibrate the whole system at least 20 ns before MD production.
CHARMM-GUI aims to provide more convenient way for NAMD or CHARMM simulation. It can generate a embeded protein/membrane system with OPM position through web page interface. It even can helps to assign CHARMM CGFF for the ligand. However, there are also some obvious weeknees for it: there are so many atom clashed between lipids that we can hardly believe the lipids are pre-equilibrated which claimed by the author; the input file provided by CHARMM-GUI is not good enough for membrane protein simulation since the whole quilibration step only contains no more than 3 ns and obvious GPCR helix movement are often observed within such short time which shouldn't expected at this time scale level. So, one have to improve the protocol by himself.
Desmond System builder tool is incorporated in Schrodinger Maestro GUI and it provides very friendly interface for users. It can build a OPM based position for protein/membrane system very easily by clicking some bottoms. It can also assign CHARMM36 FF by VIPARR tool in Desmond.
Both g_membed and InflateGro are tools within Gromacs and both of them can embed the protein into a pre-equlibrated membrane system which save lot of time for equilibration. Although g_membed is a little bit difficult than InflateGro, but the output seems to be much better than the later one.
2. Force filed
It is said that CHARMM36 FF is the best FF for lipids which is currently the only FF can reproduce lipid gel phase property. However, recent Lipid 11 FF from latest Amber 12 is also claimed to be as good as CHARMM36 FF, although related paper is being reviewed these days. Both full atom FF are quite good option for protein system simulation.
There are also other FF and methods including Gromos FF which is a united atoms FF and nowadays coarse gain MD which use dummy sphere to represent groups and accelerate the simulation dramatically (24 core workstation can even achieve up to several microsecond/day). The demerit for those methods are also obvious: we gain what we paid.
3. Topology for Ligand
This is always a headache problem for many people in MD simulation. In Desmond, ligand topology can be recognized automatically with OPLS_2005 FF. However, OPLS_2005 is only good enough for tens of ns MD simulation, it is rather poor if submit to micro second MD. If we would like to use CHARMM36 FF for protein/membrane system bound with ligand, we can generate topology from Swissparam (http://swissparam.ch/) and convert them into Desmond Viparr format by script from Desmond 2012 ($SCHRODINGER/desmond-v31023/data/viparr/converters). This tool sometimes doesn't work well, it is said that it can be fully supported by Desmond in the next version of Desmond which would be released at the beginning of next year. What's need to mention is that CHARMM CG FF is also reachable in Desmond 2012 ($SCHRODINGER/desmond-v31023/data/viparr/ff/cgenff_base_v2b7), one can build manually with those molecular templates if the target one is not so complicated.
CHARMM CG FF also could be obtained from (https://www.paramchem.org/). If the ligand structure is not so complicated, it may work well. However, it sometimes may not recognize ligand bond order and so on correctly. In this way, one have to go to CHARMM forum for helps.
Amber GAFF is definitely extremely attractive and the primary choice for a ligand bound system. When the latest LIPID 11 FF in Amber 12 come out, Amber should be the first choice for many people especially those work with ligand.
4. Efficiency
Although the hardware of computer develops so fast nowadays that CPU update one generation almost each year, the efficiency of MD simulations seems don't improve so much these days. For instance: no matter how many CPU we use, for a typical membrane protein simulation (132 lipids, 300aa protein, 50,000 atoms in all) with full atom FF and typical cutoff (9-10) with PME: Gromacs can get up to 20 ns/day (double precision), Amber 12 ns/day, NAMD 4ns/day. Desmond is an exception since the parralization is much more superior than any other MD tools, it can up to 100 ns/day with 512 CPU. It can even up to several microsecond/day in Anton with full atom FF. It would be a wise option to use either Desmond or Gromacs, if one would like to run hundreds of ns with full atom FF. Of course, it is also acceptable for Amber and NAMD CPU performance if the simulation only last for tens of ns.
GPU technology is developing quite fast in recent one or two years and it also bring exciting news for computational work especially NVIDIA CUDA accelerations. For instance, with two GTX590, Amber 12 can get up to 20ns/day while 24 core i7 3.6 GHz CPU can only get 4ns/day (with intel compiler, gnu is even much slower). NAMD on the other hand, can get 5ns/day with CUDA acceleration while 24 core i7 3.6 GHz CPU can only get 0.5 ns/day. Currently, GPU calculation is not supported in Desmond, but this feature is expected to be available in next version.
本文引用地址： http://blog.sciencenet.cn/blog-355217-596240.html
1. Assemble protein/membrane system
Many tools are now available for protein/membrane building including:
VMD (http://www.ks.uiuc.edu/Research/vmd/)
CHARMM-GUI (http://www.charmm-gui.org/)
Desmond System Builder (http://www.deshawresearch.com/resources_desmond.html)
g_membed (http://wwwuser.gwdg.de/~ggroenh/membed.html)
InflateGro (http://moose.bio.ucalgary.ca/index.php?page=Translate_lipdis)
VMD can support well for POPC and POPE membrane system building with CHARMM27 and CHARMM36 FF. However, one have to add additional solvent and ions into the system by tcl script from VMD tutorial. It will also need some script to merge membrane and protein. Moreover, since the lipids are not pre-equilirated, it would be necessary to equilibrate the whole system at least 20 ns before MD production.
CHARMM-GUI aims to provide more convenient way for NAMD or CHARMM simulation. It can generate a embeded protein/membrane system with OPM position through web page interface. It even can helps to assign CHARMM CGFF for the ligand. However, there are also some obvious weeknees for it: there are so many atom clashed between lipids that we can hardly believe the lipids are pre-equilibrated which claimed by the author; the input file provided by CHARMM-GUI is not good enough for membrane protein simulation since the whole quilibration step only contains no more than 3 ns and obvious GPCR helix movement are often observed within such short time which shouldn't expected at this time scale level. So, one have to improve the protocol by himself.
Desmond System builder tool is incorporated in Schrodinger Maestro GUI and it provides very friendly interface for users. It can build a OPM based position for protein/membrane system very easily by clicking some bottoms. It can also assign CHARMM36 FF by VIPARR tool in Desmond.
Both g_membed and InflateGro are tools within Gromacs and both of them can embed the protein into a pre-equlibrated membrane system which save lot of time for equilibration. Although g_membed is a little bit difficult than InflateGro, but the output seems to be much better than the later one.
2. Force filed
It is said that CHARMM36 FF is the best FF for lipids which is currently the only FF can reproduce lipid gel phase property. However, recent Lipid 11 FF from latest Amber 12 is also claimed to be as good as CHARMM36 FF, although related paper is being reviewed these days. Both full atom FF are quite good option for protein system simulation.
There are also other FF and methods including Gromos FF which is a united atoms FF and nowadays coarse gain MD which use dummy sphere to represent groups and accelerate the simulation dramatically (24 core workstation can even achieve up to several microsecond/day). The demerit for those methods are also obvious: we gain what we paid.
3. Topology for Ligand
This is always a headache problem for many people in MD simulation. In Desmond, ligand topology can be recognized automatically with OPLS_2005 FF. However, OPLS_2005 is only good enough for tens of ns MD simulation, it is rather poor if submit to micro second MD. If we would like to use CHARMM36 FF for protein/membrane system bound with ligand, we can generate topology from Swissparam (http://swissparam.ch/) and convert them into Desmond Viparr format by script from Desmond 2012 ($SCHRODINGER/desmond-v31023/data/viparr/converters). This tool sometimes doesn't work well, it is said that it can be fully supported by Desmond in the next version of Desmond which would be released at the beginning of next year. What's need to mention is that CHARMM CG FF is also reachable in Desmond 2012 ($SCHRODINGER/desmond-v31023/data/viparr/ff/cgenff_base_v2b7), one can build manually with those molecular templates if the target one is not so complicated.
CHARMM CG FF also could be obtained from (https://www.paramchem.org/). If the ligand structure is not so complicated, it may work well. However, it sometimes may not recognize ligand bond order and so on correctly. In this way, one have to go to CHARMM forum for helps.
Amber GAFF is definitely extremely attractive and the primary choice for a ligand bound system. When the latest LIPID 11 FF in Amber 12 come out, Amber should be the first choice for many people especially those work with ligand.
4. Efficiency
Although the hardware of computer develops so fast nowadays that CPU update one generation almost each year, the efficiency of MD simulations seems don't improve so much these days. For instance: no matter how many CPU we use, for a typical membrane protein simulation (132 lipids, 300aa protein, 50,000 atoms in all) with full atom FF and typical cutoff (9-10) with PME: Gromacs can get up to 20 ns/day (double precision), Amber 12 ns/day, NAMD 4ns/day. Desmond is an exception since the parralization is much more superior than any other MD tools, it can up to 100 ns/day with 512 CPU. It can even up to several microsecond/day in Anton with full atom FF. It would be a wise option to use either Desmond or Gromacs, if one would like to run hundreds of ns with full atom FF. Of course, it is also acceptable for Amber and NAMD CPU performance if the simulation only last for tens of ns.
GPU technology is developing quite fast in recent one or two years and it also bring exciting news for computational work especially NVIDIA CUDA accelerations. For instance, with two GTX590, Amber 12 can get up to 20ns/day while 24 core i7 3.6 GHz CPU can only get 4ns/day (with intel compiler, gnu is even much slower). NAMD on the other hand, can get 5ns/day with CUDA acceleration while 24 core i7 3.6 GHz CPU can only get 0.5 ns/day. Currently, GPU calculation is not supported in Desmond, but this feature is expected to be available in next version.
本文引用地址： http://blog.sciencenet.cn/blog-355217-596240.html