The Latest in "Hands On" Software

Several years ago, the old 'molecular modeling software' industry collapsed due to competition from free, open-source, and frequently superior tools. The new paradigm is bringing us exciting improvements in functionality and diversity, provided one knows how to use it. The only thing I miss is the 'sandbox' interface tool just just plain old hacking around with molecules. Are there any new free tools emerging to take the place of old Behemoths like SYBYL and Discovery Studio?

Go to the profile of Gerald Lushington
Apr 17, 2015
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There was a time, not that long ago, when the vast majority of computational drug discovery research professionals spent a substantial amount of their time staring at one very specific form of software window -- a molecular modeling interface. Ten years ago, there was a small handful of successful corporate solutions (e.g., Tripos, Accelrys, Schrodinger to name some of the largest) that dominated the market. The basic upshot of all of this was that regardless of whether your research was in academic, industry or government settings, there was a fair chance that you used one of these well-established tools, and paid a fair bit of money each year to do so.

Wow -- things have certainly changed! As of April 2015, if I do a Google search on "molecular modeling software" only one out of the top ten hits (HyperChem) is a commercial product. The rest of the top links are dominated either by freely distributed programs or else by lists of different resources available. What happened to the old software structure that once so dominated the computational support of medicinal chemistry research?


The precise reason for the collapse of small but once-vibrant commercial sector is difficult to pin down, but it is probably fairly telling that the old modeling environments are generally not missed. An increasingly sophisticated user base has grown more comfortable in fusing a collection of different, separately-distributed tools together in order to carry out their simulations and analysis. Thus a researcher might now use Marvin to sketch and structurally optimize a chemical's geometry, Autodock to predict how it might bind to a target receptor, and PyMol to produce publication-quality graphics of the predicted complex. The researcher has to flip between windows of the workstation, and it may feel a bit more cumbersome than the single unified environment that we once knew, but the actual calculations are typically a lot faster, and probably more reliable.

As a devout proponent and user of open source scientific software (see my Tumblr blog for proof), it would be hard to find fault with the current situation, which I believe is far more indicative of a vibrant scientific culture than the old black box era. If there's been anything that I've missed about the monolithic tools such as SYBYL, Jaguar and Discovery Studio though, it has been the facile opportunity to just goof around. By this I mean, be able to rapidly assemble and tweak a molecule, optimize it, run quick dynamics simulations to understand conformational variants, rapidly ascertain how minor functional group variations affect properties, and so forth. In other words, a computational and quantitative equivalent to an elder generation's use of solid ball and stick models. The ability to generate nice graphics to characterize interesting features of the molecule is, of course, very helpful as well.

A question that I've asked myself from time to time over recent years is whether a free (and ideally open-source) tool will emerge that serves this purpose. Below is a graphic (admittedly an unscientific kludge) that I hacked together based on my current opinions of some great but not completely satisfactory software options. The areas of scoring are pretty straightforward:

  • Builder: can you build an organic molecule or peptide without too much hassle?
  • Optimizer: can you take the hand-built molecule and convert it into a physically plausible geometry with little to no teeth-gnashing?
  • Dynamics: can you see what soft of conformations that molecule is likely to sample under different conditions of temperature and dielectric medium?
  • Graphics: can you generate and capture some nice pictures of your molecule?
Builder Optimizer Dynamics Graphics
Avogadro (version 1) 5 3 0 2
Ascalaph Designer 3 2 3 3
BallView 3 2 3 4
PyMol 3 1 0 5
Vega-ZZ 2 5 3 3


The unscientific scoring scheme I've used basically ranges from '0' (the software doesn't support this) up to '5' (in my opinion, the program does this better than any of the old commercial products once did). For reference, I probably would have given a program like SYBYL 8.1 scores of 3 and 4 across the board. As of right now, I don't think any of these free tools are quite to this level, although clearly some tools do exceed prior standard in some areas. I absolutely love Avogadro's small molecular and peptide builders (version 1 only -- there are things in version 2 that are sadly very broken!), and I use Vega-ZZ extensively, crunching out simple molecular mechanics calculations on covalent inhibitors because the program is so fast and easy). PyMol, of course, is practically an industry standard now for high quality graphics. So sad that Warren Delano didn't survive to see his legacy -- the man truly deserves to be a millionaire on a beach somewhere!

If you examine the collection as a whole (i.e., overlook the fact that each of these tools has strengths and weakness, and none is quite the 'perfect' package) you'll see that the one weakness is that none of these tools does a great job of handling molecular dynamics. My complaint, which is articulated a lot more verbosely elsewhere in this blog post, is that while three of the tools support some level of interactive dynamics monitoring, none of them make it anywhere as simple as the methodologically analogous molecular mechanics calculations. In all cases, you really have to use a separate tool such as VMD to parametrize the system, or else supposedly simpler formulations (e.g., representing the system with highly generalized CVFF or Tripos force fields) invariably fail without a helpful explanation. Perhaps what these software developers don't realize is that there's a substantial demand, not just for highly rigorous dynamics simulations that can be validated as plausibly reproducing accurate IR spectra or kinetics measurements), but also for those simple sandbox glimpses that answer intuitive questions such as, 'I wonder if this molecule might ever vibrate such that atom A gets close to atom B?' I used to use SYBYL and Insight II for goofy things like that all the time. Now it seems like I'm stuck doing a semi-publication-quality NAMD simulation every time I want to watch my molecule wobble around.

Ah well -- it's wonderful and amazing what one can get for free these days. I guess I can put up with a little less wobbling.

For those who might be interested, below are a few of my older Blog posts that provide greater information on some of the free software tools mentioned in this post:

Avogadro
BallView
Vega-ZZ

What's the Matter with Molecular Dynamics?

Go to the profile of Gerald Lushington

Gerald Lushington

Dr., LiS Consulting

Gerald Lushington has a passion for the collaborative aspects of drug design, with his greatest interests lying in the application of molecular modeling, chemical informatics and bioinformatics to problems of direct interest to molecular biology, synthetic chemistry, and chemical biology. Among the various facets of pharmacology he has made significant contributions to are genetic target validation, structural biology, chemical library optimization, molecular diversity analysis, structure-based drug design, QSAR and toxicology. In addition to his consulting activities, Lushington has adjunct faculty appointments as professor of Human Nutrition at Kansas State University, and within the Medicinal Chemistry Department at the University of Kansas. He has more than 150 peer-reviewed publications, of which at least one hundred relate fairly closely to drug discovery challenges. He serves the broader community in his role as informatics section editor for the journal Combinatorial Chemistry and High Throughput Screening, and as an informatics editor in the online reviewing service WebMed Central. Among the various journals Lushington serves in editorial advisory board capacities include BMC's Journal of Clinical Bioinformatics, Bentham's Current Bioactive Compounds, and Jacobs Journal of Drug Metabolism and Toxicology. Although Lushington collaborates with a diverse array of academic and corporate clients and partners, his most active areas of research relate to the development of microbiology therapeutics, including de novo discovery of viral protease inhibitors and in the commercialization of antimicrobial peptides.

3 Comments

Go to the profile of Jürgen Bajorath
Jürgen Bajorath over 3 years ago

I've enjoyed this post, which makes a number of interesting points. It is true that freeware for molecular modeling, comp. chem., and comp. med. chem. is becoming increasingly available; a very positive development for the field as a whole. A variety of research groups in different environments (are beginning to) promote a culture of data and software/tool sharing, often as a part of their publications. I would probably not go so far to conclude that the molecular modeling industry has "collapsed". The industry has been changing. Among others, OpenEye, Chemical Computing Group, or Schrödinger are alive (and probably continue to do quite well), but their product/service portfolio has evolved in different directions, focusing more and more on expert systems and specialized applications, beyond classical molecular mechanics, modeling, and molecular graphics. In my view, comp. chem. firms can only survive if they have scientific horsepower and promote rigorous approaches (which has not changed very much over the years). The successful ones have strong science behind their products, others disappear. It is also true that companies as the ones mentioned above have made important contributions to the scientific development of the broadly defined comp. chem. field. Clearly, the availability of many free desktop modeling tools and other programs pointed out by Gerald Lushington is making it more difficult to sell software, which is a good incentive to push the boundaries and stress scientific potential and innovation.

Go to the profile of Gerald Lushington
Gerald Lushington about 3 years ago

Since my original post, I have received some useful and notable

feedback, some of which is recorded here in this discussion space, and

the rest of which transpired in the background, via e-mail and Twitter.

I would like to share with you one comment that I will respond to and

potentially seque toward another possible topic for future

discussion.

The comment in question arose from my statement that there were no

free software tools out there that provided simple, friendly interfaces

to Molecular Dynamics simulations. While acknowledging that various

programs enabled a MD interface of some sort, nobody has provided a

robust scheme on par with SYBYL, Discovery Studio or Schrodinger.

In response to this statement. Alexei Nikitin, the lead developer of

the general molecular modeling suite, Ascalaph Designer

(http://www.biomolecular-modeling.com/Ascalaph/Ascalaph_Designer.html)

wrote me to inquire as to why I rated his software low on my original

chart, and what was I looking for in a hands-on, sandbox type program

that was not already present in his program.

Having not give Ascalaph Designer a serious look in a couple of

years,I decided to grant Dr. Nikitin the benefit of the doubt and,

indeed, I'm happy to make some revisions to my earlier assessment. Here

are some notes, beginning with my one harshest criticism and then moving

on to some gratifying positives:

1) How robust and intuitive is the molecular builder? This,

unfortunately, is Ascalaph Designer's bete noire -- the builder scheme

is quite unlike any of the rather diverse protocols I've gotten

accustomed to over the years (e.g., ChemDraw, Marvin, SYBYL, Insight-II,

Avogadro, PyMol, Vega-ZZ, etc.). It relies heavily on [shift] and

[ctrl] keys to effect one-mouse-button building in a world where most of

us have gotten very accustomed to the power of two-button and three-

button mice. It seems to lack the one-click option for changing bond-

orders that most good builders have. In fact, after fairly lengthy

experimentation and even some manual reading, I still haven't figured

out how to adjust atomic valences and bond types once they're originally

set.

2) If you get past that hurdle, however, the program is surprisingly

robust. The nicest thing about it is that, by default, it is capable of

correctly intuiting the atom and bond parameters for organic molecules

built or loaded into the viewer, and does so using the AMBER force

field! This surpasses all of the other packages that I'm aware of,

which either specify force fields in terms of simpler (more approximate)

parametrizations such as CVFF, MMFF94 or the Tripos force field. Kudos

to Dr. Nikitin for this!

3) Molecular optimization and dynamics interfaces are seamlessly

accessed from the builder, contain a decent array of options, and submit

simulations without any fuss. There are start and stop buttons for job

control, which is a very nice touch.

4) I haven't benchmarked the run-times against other programs

(ranging from dead-slow programs such as SYBYL and Avogadro up to

medium-fast ones like Insight-II/Discover and Vega-ZZ/AMMP

) but at a

first glance it appears to hold its own quite well.

In any case, based on these assessments, I now find myself modifying

my original ratings table to reflect the following:














































Builder

Optimizer

Dynamics

Graphics

Avogadro (version 1)

5

3

0

2

Ascalaph Designer

2

4

4

3

BallView

3

2

3

4

PyMol

3

1

0

5

Vega-ZZ

2

5

3

3

Go to the profile of Hypersphere
Hypersphere over 2 years ago

Thank you for an interesting post. A software package that I can heartily recommend is YASARA. I have an academic group leader license for the YASARA-Structure version. It is comprehensive, including the best graphical front-end I have seen for docking via Autodock or Autodock VINA, homology modeling, molecular dynamics, and much more. The pricing is very reasonable and the licensing is liberal and highly flexible. It also has beautiful graphics and it is extremely fast. Moreover, it is cross-platform, with versions for linux, OS X, and Windows. YASARA is now my go-to program for molecular viewing and protein modeling. It does not, however, include cheminformatics tools, so that I still need to piece together other software for doing such things as building QSAR models.