ProteinVolume: calculating molecular van der Waals and void volumes in proteins

Background

Voids and cavities in the native protein structure determine the pressure unfolding of proteins. In addition, the volume changes due to the interaction of newly exposed atoms with solvent upon protein unfolding also contribute to the pressure unfolding of proteins. Quantitative understanding of these effects is important for predicting and designing proteins with predefined response to changes in hydrostatic pressure using computational approaches. The molecular surface volume is a useful metric that describes contribution of geometrical volume, which includes van der Waals volume and volume of the voids, to the total volume of a protein in solution, thus isolating the effects of hydration for separate calculations.

Results

We developed ProteinVolume, a highly robust and easy-to-use tool to compute geometric volumes of proteins. ProteinVolume generates the molecular surface of a protein and uses an innovative flood-fill algorithm to calculate the individual components of the molecular surface volume, van der Waals and intramolecular void volumes. ProteinVolume is user friendly and is available as a web-server or a platform-independent command-line version.

Conclusions

ProteinVolume is a highly accurate and fast application to interrogate geometric volumes of proteins. ProteinVolume is a free web server available on http://gmlab.bio.rpi.edu. Free-standing platform-independent Java-based ProteinVolume executable is also freely available at this web site.

Electronic supplementary material

The online version of this article (doi:10.1186/s12859-015-0531-2) contains supplementary material, which is available to authorized users.     

Calibration of effective van der Waals atomic contact radii for proteins and peptides

Effective van der Waals radii were calibrated in such a way that molecular models built from standard bond lengths and bond angles reproduced the amino acid conformations observed by crystallography in proteins and peptides. The calibrations were based on the comparison of the Ramachandran plots prepared from high-resolution X-ray data of proteins and peptides with the allowed phi, psi torsional angle space for the dipeptide molecular models. The calibrated radii are useful as criteria with which to filter energetically improbable conformations in molecular modeling studies of proteins and peptides.     

Nature of Novel 2D van der Waals Heterostructures for Superior Potassium Ion Batteries

Novel 2D van der Waals heterostructures with innovative bimetallic oxychloride (Bi‐ and Sb‐based oxychloride) nanosheets that are well dispersed on reduced graphene oxide nanosheets, are established through element engineering for superior potassium ion battery (PIBs) anodes. This material displays an exceptional electrochemical performance, obtaining a discharge capacity as high as 360 mAh g^?1 at 100 mA g^?1 after running 1000 cycles for over 9 months with a capacity preservation percentage of 88.5% and achieving a discharge capacity as high as 319 mAh g^?1 at 1000 mA g^?1, in addition to the low charge/discharge plateaus for anodes and promising full cell performance. More significantly, the nature of such 2D van der Waals heterostructures, including the element engineering for morphology control, the function of each component of heterostructures, the mechanism of potassium ion storage, and the process of K⁺ intercalation accompanied with the lattice distortion and chemical bond breakages, is explored in depth. This study is critical for not only paving the way for the practical application of PIBs but also shedding light on fundamentals of potassium ion storage in 2D van der Waals heterostructures.     

Mixed Valence Tin Oxides as Novel van der Waals Materials: Theoretical Predictions and Potential Applications

Van der Waals (vdW) heterostructures, which can be assembled by combining 2D atomic crystals in a precisely chosen sequence, enable a wide range of potential applications in optoelectronics, photovoltaics, and photocatalysis. However, the difficulty of peeling isolated atomic planes and the lattice mismatch between different materials is the main obstacle to hinder vdW materials from more practical applications. In this work, the mixed valence tin oxides, Sn_xO_y (0.5 < x/y < 1), are proposed as a new member of vdW materials and these mixed valence tin oxides show promise to overcome the above‐mentioned obstacle. Density‐functional theory calculations are combined with an evolutionary algorithm to predict the crystal structures of a series of previously reported tin oxides (Sn₂O₃, Sn₃O₄, Sn₄O₅, and Sn₅O₆), unreported compositions (Sn₇O₈, Sn₉O₁₀, and Sn₁₁O₁₂), and a new β ‐ SnO phase. These structures consist of β‐SnO, Sn₂O₃, and Sn₃O₄ monolayers. Their band gaps can be engineered in the 1.56–3.25 eV range by stacking the monolayers appropriately. The band gap depends linearly on the interlayer distance, as understood from interlayer Sn²⁺–Sn²⁺ and intralayer Sn²⁺–O interactions. Sn_xO_y structures exhibit high photoabsorption coefficients and suitable band‐edge positions for photoexcited H₂ evolution; this indicates potential for environmentally benign solar energy conversion in photovoltaic and photocatalytic applications.     

van der Waals potential barrier for cobaltocene encapsulation into single-walled carbon nanotubes: classical molecular dynamics and ab initio study

In this work, we carried out geometry optimisations and classical molecular dynamics for the problem of cobaltocene (CC) encapsulation into different carbon nanotubes (CNTs) ((7,7), (8,8), (13,0) and (14,0) tubes were used). CCs are molecules composed of two aromatic pentagonal rings (C5H5) sandwiching one cobalt atom. From our simulation results, we observed that CC was encapsulated into CNTs (8,8), (13,0) and (14,0). However, for CNT (7,7), the encapsulation could not occur, in disaggrement with some previous works in the literature. Our results show that the encapsulation process is mainly governed by van der Waals potential barriers.     

Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions

We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were ?13.80?kcal/mol for COX-1 and ?18.46?kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.     

Importance of van der Waals contact between Glu 35 and Trp 109 to the catalytic action of human lysozyme.

The importance of van der Waals contact between Glu 35 and Trp 109 to the active-site structure and the catalytic properties of human lysozyme (HL) has been investigated by site-directed mutagenesis. The X-ray analysis of mutant HLs revealed that both the replacement of Glu 35 by Asp or Ala, and the replacement of Trp 109 by Phe or Ala resulted in a significant but localized change in the active-site cleft geometry. A prominent movement of the backbone structure was detected in the region of residues 110 to 120 and in the region of residues 100 to 115 for the mutations concerning Glu 35 and Trp 109, respectively. Accompanied by the displacement of the main-chain atoms with a maximal deviation of C alpha atom position ranging from 0.7 A to 1.0 A, the mutant HLs showed a remarkable change in the catalytic properties against Micrococcus luteus cell substrate as compared with native HL. Although the replacement of Glu 35 by Ala completely abolished the lytic activity, HL-Asp 35 mutant retained a weak but a certain lytic activity, showing the possible involvement of the side-chain carboxylate group of Asp 35 in the catalytic action. The kinetic consequence derived from the replacement of Trp 109 by Phe or Ala together with the result of the structural change suggested that the structural detail of the cleft lobe composed of the residues 100 to 115 centered at Ala 108 was responsible for the turnover in the reaction of HL against the bacterial cell wall substrate. The results revealed that the van der Waals contact between Glu 35 and Trp 109 was an essential determinant in the catalytic action of HL.     

Unveiling the Unique Phase Transformation Behavior and Sodiation Kinetics of 1D van der Waals Sb2S3 Anodes for Sodium Ion Batteries

Carbon‐coated van der Waals stacked Sb₂S₃ nanorods (SSNR/C) are synthesized by facile hydrothermal growth as anodes for sodium ion batteries (SIBs). The sodiation kinetics and phase evolution behavior of the SSNR/C anode during the first and subsequent cycles are unraveled by coupling in situ transmission electron microscopy analysis with first‐principles calculations. During the first sodiation process, Na⁺ ions intercalate into the Sb₂S₃ crystals with an ultrafast speed of 146 nm s^?1. The resulting amorphous Na_x Sb₂S₃ intermediate phases undergo sequential conversion and alloying reactions to form crystalline Na₂S, Na₃Sb, and minor metallic Sb. Upon desodiation, Na⁺ ions extract from the nanocrystalline phases to leave behind the fully desodiated Sb₂S₃ in an amorphous state. Such unique phase evolution behavior gives rise to superb electrochemical performance and leads to an unexpectedly small volume expansion of ≈54%. The first‐principles calculations reveal distinctive phase evolution arising from the synergy between the extremely low Na⁺ ion diffusion barrier of 190 meV and the sharply increased electronic conductivity upon the formation of amorphous Na_x Sb₂S₃ intermediate phases. These findings highlight an anomalous Na⁺ ion storage mechanism and shed new light on the development of high performance SIB anodes based on van der Waals crystals.     

Atomic contacts in protein structures. A detailed analysis of atomic radii, packing, and overlaps

A rigorous quantitative assessment of atomic contacts and packing in native protein structures is presented. The analysis is based on optimized atomic radii derived from a set of high-resolution protein structures and reveals that the distribution of atomic contacts and overlaps is a structural constraint in proteins, irrespective of structural or functional classification and size. Furthermore, a newly developed method for calculating packing properties is introduced and applied to sets of protein structures at different levels of resolution. The results show that limited resolution yields decreasing packing quality, which underscores the relevance of packing considerations for structure prediction, design, dynamics, and docking.     

SIMPLE estimate of the free energy change due to aliphatic mutations: superior predictions based on first principles

The bioinformatics revolution of the last decade has been instrumental in the development of empirical potentials to quantitatively estimate protein interactions for modeling and design. Although computationally efficient, these potentials hide most of the relevant thermodynamics in 5-to-40 parameters that are fitted against a large experimental database. Here, we revisit this longstanding problem and show that a careful consideration of the change in hydrophobicity, electrostatics, and configurational entropy between the folded and unfolded state of aliphatic point mutations predicts 20-30% less false positives and yields more accurate predictions than any published empirical energy function. This significant improvement is achieved with essentially no free parameters, validating past theoretical and experimental efforts to understand the thermodynamics of protein folding. Our first principle analysis strongly suggests that both the solute-solute van der Waals interactions in the folded state and the electrostatics free energy change of exposed aliphatic mutations are almost completely compensated by similar interactions operating in the unfolded ensemble. Not surprisingly, the problem of properly accounting for the solvent contribution to the free energy of polar and charged group mutations, as well as of mutations that disrupt the protein backbone remains open.     

The dominant role of side-chain backbone interactions in structural realization of amino acid code. ChiRotor: a side-chain prediction algorithm based on side-chain backbone interactions

The basic differences between the 20 natural amino acid residues are due to differences in their side-chain structures. This characteristic design of protein building blocks implies that side-chain-side-chain interactions play an important, even dominant role in 3D-structural realization of amino acid codes. Here we present the results of a comparative analysis of the contributions of side-chain-side-chain (s-s) and side-chain-backbone (s-b) interactions to the stabilization of folded protein structures within the framework of the CHARMm molecular data model. Contrary to intuition, our results suggest that side-chain-backbone interactions play the major role in side-chain packing, in stabilizing the folded structures, and in differentiating the folded structures from the unfolded or misfolded structures, while the interactions between side chains have a secondary effect. An additional analysis of electrostatic energies suggests that combinatorial dominance of the interactions between opposite charges makes the electrostatic interactions act as an unspecific folding force that stabilizes not only native structure, but also compact random conformations. This observation is in agreement with experimental findings that, in the denatured state, the charge-charge interactions stabilize more compact conformations. Taking advantage of the dominant role of side-chain-backbone interactions in side-chain packing to reduce the combinatorial problem, we developed a new algorithm, ChiRotor, for rapid prediction of side-chain conformations. We present the results of a validation study of the method based on a set of high resolution X-ray structures.     

Fractal nature of protein surface roughness: a note on quantification of change of surface roughness in active sites,before and after binding

Year 2010 marked the 25th year since we came to know that roughness of a protein surface has fractal symmetry. Ever since the publication of Lewis and Rees' paper, hundreds of works from a spectrum of perspectives have established that fractal dimension (FD) can be considered as a reliable marker that describes roughness of protein surface objectively. In this article, we introduce readers to the fundamentals of fractals and present categorical biophysical and geometrical reasons as to why FD‐based constructs can describe protein surface roughness more accurately. We then review the commonality (and the lack of it) between numerous approaches that have attempted to investigate protein surface with fractal measures, before exploring the patterns in the results that they have produced. Apart from presenting the genealogy of approaches and results, we present an analysis that quantifies the difference in surface roughness in stretches of protein surface containing the active site, before and after binding to ligands, to underline the utility of FD‐based measures further. It has been found that surface stretches containing the active site, in general, undergo a significant increment in its roughness after binding. After presenting the entire repertoire of FD‐based surface roughness studies, we talk about two yet‐unexplored problems where application of FD‐based techniques can help in deciphering underlying patterns of surface interactions. Finally, we list the limitations of FD‐based constructs and put down several precautions that one must take while working with them. Copyright © 2013 John Wiley & Sons, Ltd.     

Computational redesign of the SHV-1 beta-lactamase/beta-lactamase inhibitor protein interface

β-lactamases are enzymes that catalyze the hydrolysis of β-lactam antibiotics. β-lactamase/β-lactamase inhibitor protein (BLIP) complexes are emerging as a well characterized experimental model system for studying protein-protein interactions. BLIP is a 165 amino acid protein that inhibits several class A β-lactamases with a wide range of affinities: picomolar affinity for K1; nanomolar affinity for TEM-1, SME-1, and BlaI; but only micromolar affinity for SHV-1 β-lactamase. The large differences in affinity coupled with the availability of extensive mutagenesis data and high-resolution crystal structures for the TEM-1/BLIP and SHV-1/BLIP complexes make them attractive systems for the further development of computational design methodology. We used EGAD, a physics-based computational design program, to redesign BLIP in an attempt to increase affinity for SHV-1. Characterization of several of designs and point mutants revealed that in all cases, the mutations stabilize the interface by 10- to 1000-fold relative to wild type BLIP. The calculated changes in binding affinity for the mutants were within a mean absolute error of 0.87 kcal/mol from the experimental values, and comparison of the calculated and experimental values for a set of 30 SHV-1/BLIP complexes yielded a correlation coefficient of 0.77. Structures of the two complexes with the highest affinity, SHV-1/BLIP (E73M) and SHV-1/BLIP (E73M, S130K, S146M), are presented at 1.7 Å resolution. While the predicted structures have much in common with the experimentally determined structures, they do not coincide perfectly; in particular a salt bridge between SHV-1 D104 and BLIP K74 is observed in the experimental structures, but not in the predicted design conformations. This discrepancy highlights the difficulty of modeling salt bridge interactions with a protein design algorithm that approximates side chains as discrete rotamers. Nevertheless, while local structural features of the interface were sometimes miscalculated, EGAD is globally successful in designing complexes with increased affinity.     

Highly accurate method for ligand-binding site prediction in unbound state (apo) protein structures

This article describes a new method for predicting ligand-binding sites of proteins. The method involves calculating the van der Waals interaction energy between a protein and probes placed on the protein surface, and then clustering the probes with attractive interaction to find the energetically most favorable locus. In 80% (28/35) of the test cases, the ligand-binding site was successfully predicted on a ligand-bound protein structure, and in 77% (27/35) was successfully predicted on an unbound structure. Our method was used to successfully predict ligand-binding sites unaffected by induced-fit as long as its scales were not very large, and it contributed to a significant improvement in prediction with unbound state protein structures. This represents a significant advance over conventional methods in detecting ligand-binding sites on uncharacterized proteins. Moreover, our method can predict ligand-binding sites with a narrower locus than those achieved using conventional methods.     

Analysis of the interactions of sulfur‐containing amino acids in membrane proteins

The interactions of Met and Cys with other amino acid side chains have received little attention, in contrast to aromatic–aromatic, aromatic–aliphatic or/and aliphatic–aliphatic interactions. Precisely, these are the only amino acids that contain a sulfur atom, which is highly polarizable and, thus, likely to participate in strong Van der Waals interactions. Analysis of the interactions present in membrane protein crystal structures, together with the characterization of their strength in small‐molecule model systems at the ab‐initio level, predicts that Met–Met interactions are stronger than Met–Cys ≈ Met–Phe ≈ Cys–Phe interactions, stronger than Phe–Phe ≈ Phe–Leu interactions, stronger than the Met–Leu interaction, and stronger than Leu–Leu ≈ Cys–Leu interactions. These results show that sulfur‐containing amino acids form stronger interactions than aromatic or aliphatic amino acids. Thus, these amino acids may provide additional driving forces for maintaining the 3D structure of membrane proteins and may provide functional specificity.     

Numerical Analysis of the Adhesive Forces in Nano-Scale Structure

Nanohairs, which can be found on the epidermis of Tokay gecko＇s toes, contribute to the adhesion by means of van der Waals force, capillary force, etc. This structure has inspired many researchers to fabricate the attachable nano-scale structures. However, the efficiency of artificial nano-scale structures is not reliable sufficiently. Moreover, the mechanical parameters related to the nano-hair attachment are not yet revealed qualitatively. The mechanical parameters which have influence on the ability of adhesive nano-hairs were investigated through numerical simulation in which only van der Waals force was considered. For the numerical analysis, finite element method was utilized and van der Waals force, assumed as 12-6 Lennard-Jones potential, was implemented as the body force term in the finite element formulation.