Better computer modeling provides a new look at large biomolecules

August 20, 2001

A new method for studying the electrical landscape of large biological molecules may enable researchers to make a leap from modeling molecules of 50,000 atoms to those of more than a million atoms.

The technique, developed by Howard Hughes Medical Institute (HHMI) researchers at the University of California, San Diego (UCSD), was used to model the electrostatic properties of microtubules, which are part of the cell's structural and transport systems, and ribosomes, which are the cell's protein-making factories. The scientists say their new computer modeling method, called parallel focusing, will provide molecular biologists with a useful tool for exploring the dynamic behavior of complex biomolecules. The scientists plan to make their software widely available to the scientific community.

Electrostatic models portray how the charges on individual atoms of a molecule interact to produce a distribution of electric fields throughout the molecule. Such models have proven useful in analyzing the stability and dynamic motions of biological molecules such as proteins, DNA, RNA and ligands, as well as how they interact.

In an article published online on August 21, 2001, in Proceedings of the National Academy of Sciences, researchers led by HHMI investigator J. Andrew McCammon report that parallel focusing is a new approach to solving the Poisson-Boltzmann equation (PBE), a fundamental equation in the field of electrostatics.

"One of the problems with traditional molecular dynamics methods for simulating large systems, is that they require considerable computational effort to simulate the surrounding atoms of the aqueous solvent," said McCammon. "The Poisson-Boltzmann equation circumvents this by treating the solvent as one featureless polarizable medium -- essentially a big cloud of charge around a molecule such as a protein," he said.

According to McCammon, the effectiveness of the PBE, which is called an "implicit solvent method," has made it one of the most popular bases for electrostatic modeling. Methods to solve the equation have been limited to molecules of about 50,000 atoms because of their considerable computational demands.

In the PNAS article, however, McCammon, HHMI predoctoral fellow Nathan A. Baker and their colleagues at UCSD describe how the parallel focusing method enables solution of the PBE to be run efficiently and flexibly on parallel computers. By using massively parallel computers, researchers can divide large computations among many processors, and drastically reduce the time required to create complex models.

Electrostatic modeling typically represents the biomolecule and the PBE on a Cartesian grid. Very fast numerical methods, such as the multigrid, are then used to solve the equation on this grid. The solution on the array of grid points is then used to represent the electrostatic potential around the biomolecule.

"One can think of these electrostatic equations as being solved in a very big box that contains the grid and which is several times larger than the molecule to be modeled," said Baker. "In the parallel focusing method, we divide that box up, so that even if it's a very large box, the calculations can be done on a single processor. We have each processor solve the equations for that coarse grid and then use that low-accuracy solution to provide the boundary conditions to focus on a much smaller and finer problem on a particular partition of the mesh allocated to that particular processor."

Parallel focusing is based on theoretical work by UCSD mathematicians Randolph E. Bank and Michael J. Holst, who proved that solving a problem with a low level of accuracy over an entire domain would enable one to use that solution to get a more accurate picture on a subset of that domain, Baker said. According to Baker and McCammon, their approach enables each processor to arrive at a highly precise solution for a tiny part of a molecule, without the need to communicate with other processors in the parallel computer. Reducing or eliminating such communications is critical if parallel machines are to tackle such problems efficiently.

The parallel focusing approach allows electrostatic modeling of molecules with a very high resolution, in which each partition of the mesh represents about 0.5 Angstroms. McCammon and Baker say that the method can be used on a range of parallel computers -- from networks of workstations with relatively low-speed connections to high-performance supercomputers.

To demonstrate the utility of their approach, the scientists modeled the electrostatic charges on microtubules and ribosomes. Microtubules are hollow polymers of protein that provide a rigid support structure in the cell and serve an important role in transporting proteins throughout the cell. Ribosomes are large molecular complexes of RNA and protein that are the site of protein synthesis in the cell.

Applying their technique to a model of a 1.25-million-atom microtubule, which was composed of 90 units of the protein tubulin, revealed that electrostatic variations in the microtubule were much larger scale than those seen in individual tubulin molecules. The large-scale "undulations" in electrical potential demonstrate the value of this type of modeling technique in revealing the collective properties of large molecules, said Baker. The scientists also found that the electrostatic potential at each end of the microtubule was different. This may provide clues to the stability of microtubules, Baker said.

"Understanding microtubule instability and the mechanism by which microtubules dissociate could have therapeutic applications, since many anti-cancer drugs act to stabilize microtubules," said McCammon. The scientists also explored the variation in electrostatic potential over the binding sites of such drugs to microtubules.

The electrostatic model of the two ribosomal subunits -- one with 88,000 atoms and the other with 94,854, revealed an intricate map of positive and negative potential that could yield insights into the function of ribosomes, said the scientists.

According to McCammon, software using the new approach will soon be made available to experimental molecular biologists to help guide their research into large molecules. The scientists will also begin extending their method to model dynamic changes in molecules over time. "This approach enables investigators to do all the things they could do with electrostatic models before -- for example, exploring binding energies and associations of proteins -- on a far larger scale that is much more relevant to cellular processes," said McCammon.
-end-


Howard Hughes Medical Institute

Related Protein Articles from Brightsurf:

The protein dress of a neuron
New method marks proteins and reveals the receptors in which neurons are dressed

Memory protein
When UC Santa Barbara materials scientist Omar Saleh and graduate student Ian Morgan sought to understand the mechanical behaviors of disordered proteins in the lab, they expected that after being stretched, one particular model protein would snap back instantaneously, like a rubber band.

Diets high in protein, particularly plant protein, linked to lower risk of death
Diets high in protein, particularly plant protein, are associated with a lower risk of death from any cause, finds an analysis of the latest evidence published by The BMJ today.

A new understanding of protein movement
A team of UD engineers has uncovered the role of surface diffusion in protein transport, which could aid biopharmaceutical processing.

A new biotinylation enzyme for analyzing protein-protein interactions
Proteins play roles by interacting with various other proteins. Therefore, interaction analysis is an indispensable technique for studying the function of proteins.

Substituting the next-best protein
Children born with Duchenne muscular dystrophy have a mutation in the X-chromosome gene that would normally code for dystrophin, a protein that provides structural integrity to skeletal muscles.

A direct protein-to-protein binding couples cell survival to cell proliferation
The regulators of apoptosis watch over cell replication and the decision to enter the cell cycle.

A protein that controls inflammation
A study by the research team of Prof. Geert van Loo (VIB-UGent Center for Inflammation Research) has unraveled a critical molecular mechanism behind autoimmune and inflammatory diseases such as rheumatoid arthritis, Crohn's disease, and psoriasis.

Resurrecting ancient protein partners reveals origin of protein regulation
After reconstructing the ancient forms of two cellular proteins, scientists discovered the earliest known instance of a complex form of protein regulation.

Sensing protein wellbeing
The folding state of the proteins in live cells often reflect the cell's general health.

Read More: Protein News and Protein Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.