Tuesday, May 15, 2012

Two Fresh Reviews on Nucleic Acid Simulations.

Two new reviews have just come out headed by common names in the field of modeling nucleic acids like Michael Levitt, Jiri Sponer, and Tom Cheatham.


Modeling Nucleic Acids
Adelene YL Sim, Peter Minary, Michael Levitt
Current Opinion in Structural Biology (2012), 22, 1-6

This is a very short review, so, if you're really looking for a REVIEW on modeling nucleic acids this is not a recommended read.
Levitt's group highlights what they call, degrees of freedom (DOF), as if it was a whole field, weird..., "degrees of freedom are degrees of freedom", not a subject field.
Anyhow, that DOF part is where it gets interesting, as they point out to their recent work which goes in the direction of rigid-body analysis, although, again, they wanna call it different.
They cite two of their recent articles, one called "Modeling and Design by Hierarchical Natural Moves", and the other called "Conformational Optimization with Natural Degrees of Freedom: A Novel Stochastic Chain Closure Algorithm".

The most interesting part of the review is that they claim to have solved, what they call the "lever-arm" problem, which I suspect to be closely related to the crank-shaft effect (neatly illustrated by Mr. "I solved tRNA", i.e., Sung‐Hou Kim). They go on to say that the trick is to use only degrees of freedom which affect local conformation (?) but this selection breaks the continuity of the helix, and so that forces them to use a chain-closure algorithm. All in all it's quite hard to follow what they mean, so it leaves one intrigued to look for answers in their other papers which seem to be more meaty.



Molecular Dynamics Simulations of G-DNA and Perspectives on the Simulation of Nucleic Acid Structures
Jiří Šponer, Xiaohui Cang, Thomas E. Cheatham III
Methods (2012), XX, XX-XX

This one is a proper review with specific details on molecular dynamics using explicit solvent (water).
It seems to tell in detail the very valuable information on the miss-happenings of the Orozco corrections (ff9 + parmbsc0) to the Amber force-field for nucleic acids which result in ladder-like conformations.
It also gives a good outline of the up-to-date developments of the AMBER and CHARMM force-fields, and mentions that CHARMM seems not to be stable on G-DNA simulations, of course, just using one methodology for the solvent cage, so, remains to be seen what happens by using something different to particle mesh ewald.

Monday, May 7, 2012

More Insights into RNA Silencing. The Structure of Argonaute 2 at 2.3 Angstrom Resolution.

The Crystal Structure of Human Argonaute2
Nicole T. Schirle and Ian J. Macrae
Science (2012), 336, 1037

Schirle and Macrae have solved the structure of the protein-RNA complex called Argonaute2 using X-ray spectroscopy. This protein-RNA complex is part of the RNA Induced Silencing Complex, or RISC for short. As its name reveals RISC's task is that of silencing. What RISC silences is RNA, meaning that it blocks a process that otherwise would have been accomplished had RISC not been there. The process blocked is translation of messenger RNA (mRNA) into proteins, and this is why the process is also known as post-transcriptional regulation, since mRNA is the target, and this one molecule has to be produced in transcribing DNA to RNA.

It seems that the trick of RISC is that of carrying a short RNA (20-25 nucleotides) which will bind in a complementary fashion to an specific mRNA sequence and then make it a target for degradation. The structure solved  by the researchers at Scripps Research Institute in la Jolla, California, is that of the molecular complex present in humans.

The following movie shows the molecular complex using the protein data bank (PDB) structure 4ei1:



The script to produce the images (which are put together into a movie) using the molecular viewing program pymol follows:

#########################################
# Mauricio Esguerra                     #
# May 4, 2012                           #
#                                       #
# General pymol script to beautify      #
# molecules.                            #
#                                       #
# This script can be invoked without    #
# X11 display with:                     #
# pymol -qc bla.pml >& bla.log &        #
#########################################


#########################################
# Molecule Specific Commands
#########################################
load 4ei1.pdb
load blocks.r3d
hide everything
create protein, chain A
create nucleic, chain B and (not resn U)
remove 4ei1 in protein
remove 4ei1 in nucleic
show cartoon
show cgo
show surface, protein
set transparency, 0.5, protein
set cartoon_ladder_mode, 0
set cartoon_rect_width, 1.2
set cartoon_rect_length, 0.9
set cartoon_cylindrical_helices, 1
set stick_radius, 0.14
show sticks, nucleic


#########################################
# General settings
#########################################
set orthoscopic, 1


#########################################
# Protein Secondary Structure Coloring 
#########################################
color blue, ss h
color red,  ss s
color grey, ss l+''
color black, nucleic


#########################################
# Movie Making
#########################################
unset movie_auto_interpolate
unset movie_loop

mset 1 x480

# Zoom to full and call it frame 1
zoom complete=1
frame 1
mview store

# zoom and stay
zoom nucleic, complete=1
frame 70
mview store
frame 90
mview store

mview interpolate




# from frame 101 to 315 turn in y
frame 200
turn y, 140
mview store

# from frame 316 to 480 turn in y
frame 315
turn z, 90
mview store
mview interpolate, power=1

zoom state=-1
frame 480
mview store
#frame 480
#mview store


set movie_loop
mview interpolate

mview smooth

#mplay
#mstop

#Make images for movie
viewport 1024,768
set ray_trace_frames=1
set cache_frame=0
mpng mov

A nice perspective called:
"Guided Tour to the Heart of RISC"
written by Emine Kaya and Jennifer A. Doudna accompanies the discovery reports in the same issue of science.