Stephen A. Wells

Constrained geometric simulation of diffusive motion in proteins

We describe a new computational method, FRODA (framework rigidity optimized dynamic algorithm), for exploring the internal mobility of proteins. The rigid regions in the protein are first determined, and then replaced by ghost templates which are used to guide the movements of the atoms in the protein. Using random moves, the available conformational phase space of a 100 residue protein can be well explored in approximately 10-100 min of computer time using a single processor. All of the covalent, hydrophobic and hydrogen bond constraints are maintained, and van der Waals overlaps are avoided, throughout the simulation. We illustrate the results of a FRODA simulation on barnase, and show that good agreement is obtained with nuclear magnetic resonance experiments. We additionally show how FRODA can be used to find a pathway from one conformation to another. This directed dynamics is illustrated with the protein dihydrofolate reductase.

The Database of Macromolecular Motions: new features added at the decade mark

The database of molecular motions, MolMovDB (), has been in existence for the past decade. It classifies macromolecular motions and provides tools to interpolate between two conformations (the Morph Server) and predict possible motions in a single structure. In 2005, we expanded the services offered on MolMovDB. In particular, we further developed the Morph Server to produce improved interpolations between two submitted structures. We added support for multiple chains to the original adiabatic mapping interpolation, allowing the analysis of subunit motions. We also added the option of using FRODA interpolation, which allows for more complex pathways, potentially overcoming steric barriers. We added an interface to a hinge prediction service, which acts on single structures and predicts likely residue points for flexibility. We developed tools to relate such points of flexibility in a structure to particular key residue positions, i.e. active sites or highly conserved positions. Lastly, we began relating our motion classification scheme to function using descriptions from the Gene Ontology Consortium.

A study of Fe-B and Fe-Co-B alloy particles produced by reduction with borohydride

Fe-B and Fe-CO-B alloy particles have been prepared by reduction of metal ions in aqueous solution by use of KBH4 and NaBH4. It is shown that the boron content in the particles can be varied by changing the concentration of borohydride and the Fe/Co ratio. For the lowest boron concentrations a mixture of crystalline and amorphous alloysis formed. For higher boron concentrations all the material is amorphous.

Amorphous to crystalline transformation of ultrafine Fe62B38 particles

Abstract Fe 62 B 38 particles, with sizes of 10–200 nm, have been produced by chemical reduction of Fe(II) ions in aqueous solution by KBH 4 . Electron and X-ray diffraction, X-ray absorption fine structure and Mossbauer spectroscopy results reveal that the particles are amorphous. The Mossbauer parameters and the estimates of temperatures for crystallization and for ferromagnetic to paramagnetic transition suggest that the amorphous structures are similar for the particles and ribbons or films produced by liquid-squench or sputtering. The increase of the magnetic hyperfine field with annealing temperature, as deduced from 57 Fe Mossbauer spectroscopy, is attributed to atomic rearrangement in the amorphous phase. Crystalline Fe 2 B and α-Fe are the products when the particles are annealed in Ar and H 2 at around 715 K. It is proposed that iron and boron partly separate during the initial stages of crystallization and subsequently form Fe 2 B. Passivation of the particles makes them oxidatively stable, even when heated in air at temperatures up to 650 K.

Finding best-fit polyhedral rotations with geometric algebra

There are many minerals whose structure is well described as a framework of linked SiO4 tetrahedra. Since the energy cost of stretching the Si-O bond is much greater than the cost of changing the bridging Si-O-Si bond angle, these structures may to a first approximation be analysed using the rigid-unit picture, in which the polyhedra are treated as completely rigid. In order to compare the predictions of rigid-unit theory with the results of other forms of simulation, we wish to determine how well a given set of atomic motions can be described in terms of rigid-unit motion. We present a set of techniques for finding the polyhedral rotations that most closely fit a given set of atomic motions, and for quantifying the residual distortion of the polyhedra. The formalism of geometric (Clifford) algebra proved very convenient for handling arbitrary rotations, and we use this formalism in our rotor-fitting analysis.

Real-space rigid-unit-mode analysis of dynamic disorder in quartz, cristobalite and amorphous silica

We use a recently developed tool based on geometric algebra to analyse the phase transition in quartz, the nature of the disordered high-temperature phase of cristobalite and the dynamics of silica glass. The approach is to analyse configurations generated by the reverse Monte Carlo or molecular dynamics simulations in terms of rigid-unit-mode (RUM) motions, but concentrating on quantifying the real-space distortions rather than performing a reciprocal-space analysis in terms of RUM phonons. One of the important results is a measure of the extent to which the amplitudes of motion are directly attributable to RUMs, and how the RUM fraction changes as a result of a phase transition.

Protein flexibility is key to cisplatin crosslinking in calmodulin.

Chemical crosslinking in combination with Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) has significant potential for studying protein structures and protein–protein interactions. Previously, cisplatin has been shown to be a crosslinker and crosslinks multiple methionine (Met) residues in apo‐calmodulin (apo‐CaM). However, the inter‐residue distances obtained from nuclear magnetic resonance structures are inconsistent with the measured distance constraints by crosslinking. Met residues lie too far apart to be crosslinked by cisplatin. Here, by combining FTICR MS with a novel computational flexibility analysis, the flexible nature of the CaM structure is found to be key to cisplatin crosslinking in CaM. It is found that the side chains of Met residues can be brought together by flexible motions in both apo‐CaM and calcium‐bound CaM (Ca4‐CaM). The possibility of cisplatin crosslinking Ca4‐CaM is then confirmed by MS data. Therefore, flexibility analysis as a fast and low‐cost computational method can be a useful tool for predicting crosslinking pairs in protein crosslinking analysis and facilitating MS data analysis. Finally, flexibility analysis also indicates that the crosslinking of platinum to pairs of Met residues will effectively close the nonpolar groove and thus will likely interfere with the binding of CaM to its protein targets, as was proved by comparing assays for cisplatin‐modified/unmodified CaM binding to melittin. Collectively, these results suggest that cisplatin crosslinking of apo‐CaM or Ca4‐CaM can inhibit the ability of CaM to recognize its target proteins, which may have important implications for understanding the mechanism of tumor resistance to platinum anticancer drugs.

Exploring the energy landscapes of protein folding simulations with Bayesian computation

Nested sampling is a Bayesian sampling technique developed to explore probability distributions localized in an exponentially small area of the parameter space. The algorithm provides both posterior samples and an estimate of the evidence (marginal likelihood) of the model. The nested sampling algorithm also provides an efficient way to calculate free energies and the expectation value of thermodynamic observables at any temperature, through a simple post processing of the output. Previous applications of the algorithm have yielded large efficiency gains over other sampling techniques, including parallel tempering. In this article, we describe a parallel implementation of the nested sampling algorithm and its application to the problem of protein folding in a Gō-like force field of empirical potentials that were designed to stabilize secondary structure elements in room-temperature simulations. We demonstrate the method by conducting folding simulations on a number of small proteins that are commonly used for testing protein-folding procedures. A topological analysis of the posterior samples is performed to produce energy landscape charts, which give a high-level description of the potential energy surface for the protein folding simulations. These charts provide qualitative insights into both the folding process and the nature of the model and force field used.

Reverse Monte Carlo with geometric analysis – RMC+GA

An analysis of simulated framework structures based on the rigid-unit model quantifies the distortion of polyhedra from their ideal geometric forms and decomposes the motions of the structure into components of rigid-unit displacement, rigid-unit rotation and distortion. Case studies analysing the behaviour of quartz and of other silicates demonstrate that the method provides a novel way of extracting information from reverse Monte Carlo simulations. A program called GASP has been developed to perform this analysis and is freely available to researchers. Rotations are handled using the rotor method of geometric algebra.

Ultrafine maghemite particles. I. Studies of induced magnetic texture

A sample with an orientational magnetic texture was prepared by freezing a ferrofluid containing maghemite particles in a magnetic field. The degree of alignment of the easy directions obtained by field-cooling was examined by Mossbauer spectroscopy for varying strengths of the freezing field. We compare the results with the predictions of a simple model assuming that the intrinsic magnetic anisotropy in the particles is uniaxial and that the particles are non-interacting. Good agreement between the experimental results and the theoretical model is found. This allows a determination of the magnetic anisotropy energy constant of the particles, which is an important parameter in the model. The anisotropy energy constant is also determined from the reduction of the magnetic hyperfine field relative to the saturation value caused by collective magnetic excitations, as well as from a decay of remanence measurement. Good agreement between the estimates of the anisotropy energy constant by the three methods is found.