Recombinant Virus-like Particles of Human Parvovirus B19 with the Internal Location of VP1 Unique Region Produced by Hansenula polymorpha.

Human parvovirus B19 (HPV B19) is pathogenic to human, which can cause fifth disease, transient aplastic crisis, arthritis, myocarditis, autoimmune disorders, hydrops fetalis, and so on. Currently, no approved vaccines or antiviral drugs are available against HPV B19, and thus the development of effective vaccines is needed. The capsid of HPV B19 is composed of two types of proteins, i.e., the major capsid protein VP2 and the minor protein VP1. Previous experimental studies have shown that the dominant immune responses against HPV B19 are elicited by VP1, especially the unique region on the N-terminus of VP1. It has been found that VP2 alone or VP2 and VP1 together can assemble into virus-like particle (VLP). The VLP structure formed by VP2 has been resolved, however, the location of VP1 in the capsid, especially the location of VP1 unique region with strong immunogenicity, is still not clear. In the present work, using the Hansenula polymorpha expression system developed by our laboratory, two kinds of recombinant HPV B19 VLPs were expressed, i.e., the VLP co-assembled by VP1 and VP2 (VP1/VP2 VLP) and the VLP whose VP1 content was improved (VP1h/VP2 VLP). The expression, purity, and morphology of these two VLPs were characterized, and then their immunogenic properties were investigated and compared with those of the VLP containing VP2 alone (VP2 VLP) previously developed by our group. Furthermore, the location of the VP1 unique region in the VLPs was determined by using the immunogold electron microscopy (IGEM). Our experimental results show that the VP1h/VP2 VLP elicits a stronger neutralization against the HPV B19 than VP2 and VP1/VP2 VLPs, which implies that the increase of VP1 content significantly improves the level of neutralizing antibodies. In addition, the IGEM observations suggest that the unique region of VP1 may be located inside the recombinant VLP. The VLPs recombinantly expressed by our Hansenula polymorpha system may serve as a promising candidate immunogen for HPV B19 vaccine development.

Interpreting the Dynamics of Binding Interactions of snRNA and U1A Using a Coarse-Grained Model.

The binding interactions of small nuclear RNAs (snRNA) and the associated protein factors are critical to the function of spliceosomes in alternatively splicing primary RNA transcripts. Although molecular dynamics simulations are a powerful tool to interpret the mechanism of biological processes, the atomic-level simulations are, however, too expensive and with limited accuracy for the large-size systems, such as snRNA-protein complexes. We extend the coarse-grained Gaussian network model, which models the RNA-protein complexes as a harmonic chain of Cα, P, and O4' atoms, to investigating the impact of the snRNA-binding interaction on the dynamic stability of the human U1A protein, which is a major component of the spliceosomal U1 small nuclear ribonucleoprotein particle. The results reveal that the first and third loops and the C-terminal helix regions of the U1A domain undergo a significant loss of flexibility upon the RNA binding due to the forming of mostly electrostatic and hydrogen bond interactions with RNA 5' stem and loop. By examining the residues whose mutations significantly change the binding free energy between U1A and snRNA, the Gaussian network model-based calculations show that not only the residues at the binding sites that are traditionally considered to play a major role in U1A-RNA association but also those residues that are far away from the RNA-binding interface can participate in the long-range allosteric signal transmission; these calculations are quantitatively consistent with the data observed in the recent snRNA binding experiments. The study demonstrates a useful avenue to utilize the simplified elastic network model to investigate the dynamics characteristics of the biologically important macromolecular interactions.

Structural and dynamic properties of water molecules in a uniformly charged nanopore.

The structural and dynamic properties of water molecules in a uniformly charged nanopore have been studied using the method of classical molecular dynamics simulation. When confined in an uncharged nanopore with an appropriate radius, water molecules are aligned along the nanopore axis and form a single-file structure with the dipole vectors pointing toward the same end of the nanopore. We demonstrate here that when the nanopore is uniformly charged, the water molecules in the nanopore pack more tightly and the water molecules near the two ends of the nanopore are no longer aligned along the nanopore axis but tend to be aligned perpendicularly to the nanopore axis. The water dipole vectors do not point toward the same nanopore end. When the nanopore is positively charged, the water molecules in the nanopore align with their oxygen atoms pointing to the center of the nanopore. The central water molecule forms an L-defect. However for a negatively charged nanopore, the water molecules in the nanopore take up the opposite orientation. A D-defect is formed at the center of the nanopore. Furthermore, the water molecules in the negatively charged nanopore with moderate atomic partial charges diffuse and transport more quickly than the water molecules in an uncharged nanopore.

Allosteric-activation mechanism of BK channel gating ring triggered by calcium ions.

Calcium ions bind at the gating ring which triggers the gating of BK channels. However, the allosteric mechanism by which Ca2+ regulates the gating of BK channels remains obscure. Here, we applied Molecular Dynamics (MD) and Targeted MD to the integrated gating ring of BK channels, and achieved the transition from the closed state to a half-open state. Our date show that the distances of the diagonal subunits increase from 41.0 Å at closed state to 45.7Å or 46.4 Å at a half-open state. It is the rotatory motion and flower-opening like motion of the gating rings which are thought to pull the bundle crossing gate to open ultimately. Compared with the 'Ca2+ bowl' at RCK2, the RCK1 Ca2+ sites make more contribution to opening the channel. The allosteric motions of the gating ring are regulated by three group of interactions. The first weakened group is thought to stabilize the close state; the second strengthened group is thought to stabilize the open state; the third group thought to lead AC region forming the CTD pore to coordinated motion, which exquisitely regulates the conformational changes during the opening of BK channels by Ca2+.

The impacts of surface polarity on the solubility of nanoparticle.

In order to study the dependence of water solubility and hydration behavior of nanoparticles on their surface polarity, we designed polar nanoparticles with varying surface polarity by assigning atomic partial charge to the surface of C60. The water solubility of the nanoparticle is enhanced by several orders of magnitude after the introduction of surface polarity. Nevertheless, when the atomic partial charge grows beyond a certain value (qM), the solubility continuously decreases to the level of nonpolar nanoparticle. It should be noted that such qM is comparable with atomic partial charge of a variety of functional groups. The hydration behaviors of nanoparticles were then studied to investigate the non-monotonic dependence of solubility on the surface polarity. The interaction between the polar nanoparticle and the hydration water is stronger than the nonpolar counterpart, which should facilitate the dissolution of the nanoparticles. On the other hand, the surface polarity also reduces the interaction of hydration water with the other water molecules and enhances the interaction between the nanoparticles which may hinder their dispersion. Besides, the introduction of surface polarity disturbs and even rearranges the hydration structure of nonpolar nanoparticle. Interestingly, the polar nanoparticle with less ordered hydration structure tends to have higher water solubility.

Effects of ligand binding on the mechanical stability of protein GB1 studied by steered molecular dynamics simulation.

Regulation of the mechanical properties of proteins plays an important role in many biological processes, and sheds light on the design of biomaterials comprised of protein. At present, strategies to regulate protein mechanical stability focus mainly on direct modulation of the force-bearing region of the protein. Interestingly, the mechanical stability of GB1 can be significantly enhanced by the binding of Fc fragments of human IgG antibody, where the binding site is distant from the force-bearing region of the protein. The mechanism of this long-range allosteric control of protein mechanics is still elusive. In this work, the impact of ligand binding on the mechanical stability of GB1 was investigated using steered molecular dynamics simulation, and a mechanism underlying the enhanced protein mechanical stability is proposed. We found that the external force causes deformation of both force-bearing region and ligand binding site. In other words, there is a long-range coupling between these two regions. The binding of ligand restricts the distortion of the binding site and reduces the deformation of the force-bearing region through a long-range allosteric communication, which thus improves the overall mechanical stability of the protein. The simulation results are very consistent with previous experimental observations. Our studies thus provide atomic-level insights into the mechanical unfolding process of GB1, and explain the impact of ligand binding on the mechanical properties of the protein through long-range allosteric regulation, which should facilitate effective modulation of protein mechanical properties.

Approach to the unfolding and folding dynamics of add A-riboswitch upon adenine dissociation using a coarse-grained elastic network model.

Riboswitches are noncoding mRNA segments that can regulate the gene expression via altering their structures in response to specific metabolite binding. We proposed a coarse-grained Gaussian network model (GNM) to examine the unfolding and folding dynamics of adenosine deaminase (add) A-riboswitch upon the adenine dissociation, in which the RNA is modeled by a nucleotide chain with interaction networks formed by connecting adjoining atomic contacts. It was shown that the adenine binding is critical to the folding of the add A-riboswitch while the removal of the ligand can result in drastic increase of the thermodynamic fluctuations especially in the junction regions between helix domains. Under the assumption that the native contacts with the highest thermodynamic fluctuations break first, the iterative GNM simulations showed that the unfolding process of the adenine-free add A-riboswitch starts with the denature of the terminal helix stem, followed by the loops and junctions involving ligand binding pocket, and then the central helix domains. Despite the simplified coarse-grained modeling, the unfolding dynamics and pathways are shown in close agreement with the results from atomic-level MD simulations and the NMR and single-molecule force spectroscopy experiments. Overall, the study demonstrates a new avenue to investigate the binding and folding dynamics of add A-riboswitch molecule which can be readily extended for other RNA molecules.

Tuning water transport through nanochannels by changing the direction of an external electric field.

The transport properties of water through a nanochannel influenced by the direction of an external electric field has been investigated by using molecular dynamics simulations. Water molecules flow unidirectionally across the nanochannel under a uniform external electric field without an osmotic pressure. It is found that the direction of the external field plays an important role in the interactions and dipole orientations of water molecules in the nanochannel, accordingly changing the net water flux dramatically. Most importantly, a critical angle (θC) between the external field and the nanochannel axis is found. The average net water flux increases as θ increases for θ≤θC but decreases sharply to a near-zero value for a further increase of θ. The maximum value of the average net water flux is 7.33 times as high as the value when the electric field is along the nanochannel axis. Our findings are of great practical importance for nanomolecular engineering, which provide a possible strategy for designing novel controllable water nanopumps.

Impacts of the charged residues mutation S48E/N62H on the thermostability and unfolding behavior of cold shock protein: insights from molecular dynamics simulation with Go model.

The cold shock protein from the hyperthermophile Thermotoga maritima (Tm-Csp) exhibits significantly higher thermostability than its homologue from the thermophile Bacillus caldolyticus (Bc-Csp). Experimental studies have shown that the electrostatic interactions unique to Tm-Csp are responsible for improving its thermostability. In the present work, the favorable charged residues in Tm-Csp were grafted into Bc-Csp by a double point mutation of S48E/N62H, and the impacts of the mutation on the thermostability and unfolding/folding behavior of Bc-Csp were then investigated by using a modified Go model, in which the electrostatic interactions between charged residues were considered in the model. Our simulation results show that this Tm-Csp-like charged residue mutation can effectively improve the thermostability of Bc-Csp without changing its two-state folding mechanism. Besides that, we also studied the unfolding kinetics and unfolding/folding pathway of the wild-type Bc-Csp and its mutant. It is found that this charged residue mutation obviously enhanced the stability of the C-terminal region of Bc-Csp, which decreases the unfolding rate and changes the unfolding/folding pathway of the protein. Our studies indicate that the thermostability, unfolding kinetics and unfolding/folding pathway of Bc-Csp can be artificially changed by introducing Tm-Csp-like favorable electrostatic interactions into Bc-Csp.

Domain Motions and Functionally-Key Residues of L-Alanine Dehydrogenase Revealed by an Elastic Network Model.

Mycobacterium tuberculosis L-alanine dehydrogenase (L-MtAlaDH) plays an important role in catalyzing L-alanine to ammonia and pyruvate, which has been considered to be a potential target for tuberculosis treatment. In the present work, the functional domain motions encoded in the structure of L-MtAlaDH were investigated by using the Gaussian network model (GNM) and the anisotropy network model (ANM). The slowest modes for the open-apo and closed-holo structures of the enzyme show that the domain motions have a common hinge axis centered in residues Met133 and Met301. Accompanying the conformational transition, both the 1,4-dihydronicotinamide adenine dinucleotide (NAD)-binding domain (NBD) and the substrate-binding domain (SBD) move in a highly coupled way. The first three slowest modes of ANM exhibit the open-closed, rotation and twist motions of L-MtAlaDH, respectively. The calculation of the fast modes reveals the residues responsible for the stability of the protein, and some of them are involved in the interaction with the ligand. Then, the functionally-important residues relevant to the binding of the ligand were identified by using a thermodynamic method. Our computational results are consistent with the experimental data, which will help us to understand the physical mechanism for the function of L-MtAlaDH.

The Intrinsic Dynamics and Unfolding Process of an Antibody Fab Fragment Revealed by Elastic Network Model.

Antibodies have been increasingly used as pharmaceuticals in clinical treatment. Thermal stability and unfolding process are important properties that must be considered in antibody design. In this paper, the structure-encoded dynamical properties and the unfolding process of the Fab fragment of the phosphocholine-binding antibody McPC603 are investigated by use of the normal mode analysis of Gaussian network model (GNM). Firstly, the temperature factors for the residues of the protein were calculated with GNM and then compared with the experimental measurements. A good result was obtained, which provides the validity for the use of GNM to study the dynamical properties of the protein. Then, with this approach, the mean-square fluctuation (MSF) of the residues, as well as the MSF in the internal distance (MSFID) between all pairwise residues, was calculated to investigate the mobility and flexibility of the protein, respectively. It is found that the mobility and flexibility of the constant regions are higher than those of the variable regions, and the six complementarity-determining regions (CDRs) in the variable regions also exhibit relative large mobility and flexibility. The large amplitude motions of the CDRs are considered to be associated with the immune function of the antibody. In addition, the unfolding process of the protein was simulated by iterative use of the GNM. In our method, only the topology of protein native structure is taken into account, and the protein unfolding process is simulated through breaking the native contacts one by one according to the MSFID values between the residues. It is found that the flexible regions tend to unfold earlier. The sequence of the unfolding events obtained by our method is consistent with the hydrogen-deuterium exchange experimental results. Our studies imply that the unfolding behavior of the Fab fragment of antibody McPc603 is largely determined by the intrinsic dynamics of the protein.

Molecular simulation assisted identification of Ca(2+) binding residues in TMEM16A.

Calcium-activated chloride channels (CaCCs) play vital roles in a variety of physiological processes. Transmembrane protein 16A (TMEM16A) has been confirmed as the molecular counterpart of CaCCs which greatly pushes the molecular insights of CaCCs forward. However, the detailed mechanism of Ca(2+) binding and activating the channel is still obscure. Here, we utilized a combination of computational and electrophysiological approaches to discern the molecular mechanism by which Ca(2+) regulates the gating of TMEM16A channels. The simulation results show that the first intracellular loop serves as a Ca(2+) binding site including D439, E444 and E447. The experimental results indicate that a novel residue, E447, plays key role in Ca(2+) binding. Compared with WT TMEM16A, E447Y produces a 30-fold increase in EC50 of Ca(2+) activation and leads to a 100-fold increase in Ca(2+) concentrations that is needed to fully activate the channel. The following steered molecular dynamic (SMD) simulation data suggests that the mutations at 447 reduce the Ca(2+) dissociation energy. Our results indicated that both the electrical property and the size of the side-chain at residue 447 have significant effects on Ca(2+) dependent gating of TMEM16A.

Conformational Motions and Functionally Key Residues for Vitamin B12 Transporter BtuCD-BtuF Revealed by Elastic Network Model with a Function-Related Internal Coordinate.

BtuCD-BtuF from Escherichia coli is a binding protein-dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporter system that uses the energy of ATP hydrolysis to transmit vitamin B12 across cellular membranes. Experimental studies have showed that during the transport cycle, the transporter undergoes conformational transitions between the "inward-facing" and "outward-facing" states, which results in the open-closed motions of the cytoplasmic gate of the transport channel. The opening-closing of the channel gate play critical roles for the function of the transporter, which enables the substrate vitamin B12 to be translocated into the cell. In the present work, the extent of opening of the cytoplasmic gate was chosen as a function-related internal coordinate. Then the mean-square fluctuation of the internal coordinate, as well as the cross-correlation between the displacement of the internal coordinate and the movement of each residue in the protein, were calculated based on the normal mode analysis of the elastic network model to analyze the function-related motions encoded in the structure of the system. In addition, the key residues important for the functional motions of the transporter were predicted by using a perturbation method. In order to facilitate the calculations, the internal coordinate was introduced as one of the axes of the coordinate space and the conventional Cartesian coordinate space was transformed into the internal/Cartesian space with linear approximation. All the calculations were carried out in this internal/Cartesian space. Our method can successfully identify the functional motions and key residues for the transporter BtuCD-BtuF, which are well consistent with the experimental observations.

A Peptide-Coated Gold Nanocluster Exhibits Unique Behavior in Protein Activity Inhibition.

Gold nanoclusters (AuNCs) can be primed for biomedical applications through functionalization with peptide coatings. Often anchored by thiol groups, such peptide coronae not only serve as passivators but can also endow AuNCs with additional bioactive properties. In this work, we use molecular dynamics simulations to study the structure of a tridecapeptide-coated Au25 cluster and its subsequent interactions with the enzyme thioredoxin reductase 1, TrxR1. We find that, in isolation, both the distribution and conformation of the coating peptides fluctuate considerably. When the coated AuNC is placed around TrxR1, however, the motion of the highly charged peptide coating (+5e/peptide) is quickly biased by electrostatic attraction to the protein; the asymmetric coating acts to guide the nanocluster's diffusion toward the enzyme's negatively charged active site. After the AuNC comes into contact with TrxR1, its peptide corona spreads over the protein surface to facilitate stable binding with protein. Though individual salt bridge interactions between the tridecapeptides and TrxR1 are transient in nature, the cooperative binding of the peptide-coated AuNC is very stable, overall. Interestingly, the biased corona peptide motion, the spreading and the cooperation between peptide extensions observed in AuNC binding are reminiscent of bacterial stimulus-driven approaching and adhesion mechanisms mediated by cilia. The prevailing AuNC binding mode we characterize also satisfies a notable hydrophobic interaction seen in the association of thioredoxin to TrxR1, providing a possible explanation for the AuNC binding specificity observed in experiments. Our simulations thus suggest this peptide-coated AuNC serves as an adept thioredoxin mimic that extends an array of auxiliary structural components capable of enhancing interactions with the target protein in question.

Cation-pi interactions at non-redundant protein--RNA interfaces.

Cation-pi interactions have proved to be important in proteins and protein-ligand complexes. Here, cation-pi interactions are analyzed for 282 non-redundant protein-RNA interfaces. The statistical results show that this kind of interactions exists in 65% of the interfaces. The four RNA bases are ranked as Gua>Ade>Ura>Cyt according to their propensity to participate in cation-pi interactions. The corresponding ranking for the involved amino acid residues is: Arg>Lys>Asn>Gln. The same trends are obtained based on the empirical energy calculation. The Arg-Gua pairs have the greatest stability and are also most frequently observed. The number of cation-pi pairs involving unpaired bases is 2.5 times as many as those involving paired bases. Hence, cation-pi interactions show sequence and structural specificities. For the bicyclic bases, Gua and Ade, their 5-atom rings participate in cation-pi interactions somewhat more than the 6-atom rings, with percentages of 54 and 46%, respectively, which is due to the higher cation-pi participation proportion (63%) of 5-atom rings in the paired bases. These results give a general view of cation-pi interactions at protein-RNA interfaces and are helpful in understanding the specific recognition between protein and RNA.

Supramolecular adducts of squaraine and protein for noninvasive tumor imaging and photothermal therapy in vivo.

Extensive efforts have been devoted to the development of near-infrared (NIR) dye-based imaging probes and/or photothermal agents for cancer theranostics in vivo. However, the intrinsic chemical instability and self-aggregation properties of NIR dyes in physiological condition limit their widely applications in the pre-clinic study in living animals. Squaraine dyes are among the most promising NIR fluorophores with high absorption coefficiencies, bright fluorescence and photostability. By introducing dicyanovinyl groups into conventional squaraine (SQ) skeleton. These acceptor-substituted SQ dyes not only show superior NIR fluorescence properties (longer wavelength, higher quantum yield) but also exhibit more chemical robustness. In this work, we demonstrated highly stable and biocompatible supramolecular adducts of SQ and the natural carrier protein, i.e., bovine serum albumin (BSA) (SQ⊂BSA) for tumor targeted imaging and photothermal therapy in vivo. SQ was selectively bound to BSA hydrophobic domain via hydrophobic and hydrogen bonding interactions with up to 80-fold enhanced fluorescence intensity. By covalently conjugating target ligands to BSA, the SQ⊂BSA was capable of targeting tumor sites and allowed for monitoring the time-dependent biodistribution of SQ⊂BSA, which consequently determined the protocol of photothermal therapy in vivo. We envision that this supramolecular strategy for selectively binding functional imaging agents and/or drugs into human serum albumin might potentially utilize in the preclinical and even clinic studies in the future.

Is it possible to stabilize a thermophilic protein further using sequences and structures of mesophilic proteins: a theoretical case study concerning DgAS.

Incorporating structural elements of thermostable homologs can greatly improve the thermostability of a mesophilic protein. Despite the effectiveness of this method, applying it is often hampered. First, it requires alignment of the target mesophilic protein sequence with those of thermophilic homologs, but not every mesophilic protein has a thermophilic homolog. Second, not all favorable features of a thermophilic protein can be incorporated into the structure of a mesophilic protein. Furthermore, even the most stable native protein is not sufficiently stable for industrial applications. Therefore, creating an industrially applicable protein on the basis of the thermophilic protein could prove advantageous. Amylosucrase (AS) can catalyze the synthesis of an amylose-like polysaccharide composed of only α-1,4-linkages using sucrose as the lone energy source. However, industrial development of AS has been hampered owing to its low thermostability. To facilitate potential industrial applications, the aim of the current study was to improve the thermostability of Deinococcus geothermalis amylosucrase (DgAS) further; this is the most stable AS discovered to date. By integrating ideas from mesophilic AS with well-established protein design protocols, three useful design protocols are proposed, and several promising substitutions were identified using these protocols. The successful application of this hybrid design method indicates that it is possible to stabilize a thermostable protein further by incorporating structural elements of less-stable homologs.

Insight into the structure, dynamics and the unfolding property of amylosucrases: implications of rational engineering on thermostability.

Amylosucrase (AS) is a kind of glucosyltransferases (E.C. 2.4.1.4) belonging to the Glycoside Hydrolase (GH) Family 13. In the presence of an activator polymer, in vitro, AS is able to catalyze the synthesis of an amylose-like polysaccharide composed of only α-1,4-linkages using sucrose as the only energy source. Unlike AS, other enzymes responsible for the synthesis of such amylose-like polymers require the addition of expensive nucleotide-activated sugars. These properties make AS an interesting enzyme for industrial applications. In this work, the structures and topology of the two AS were thoroughly investigated for the sake of explaining the reason why Deinococcus geothermalis amylosucrase (DgAS) is more stable than Neisseria polysaccharea amylosucrase (NpAS). Based on our results, there are two main factors that contribute to the superior thermostability of DgAS. On the one hand, DgAS holds some good structural features that may make positive contributions to the thermostability. On the other hand, the contacts among residues of DgAS are thought to be topologically more compact than those of NpAS. Furthermore, the dynamics and unfolding properties of the two AS were also explored by the gauss network model (GNM) and the anisotropic network model (ANM). According to the results of GNM and ANM, we have found that the two AS could exhibit a shear-like motion, which is probably associated with their functions. What is more, with the discovery of the unfolding pathway of the two AS, we can focus on the weak regions, and hence designing more appropriate mutations for the sake of thermostability engineering. Taking the results on structure, dynamics and unfolding properties of the two AS into consideration, we have predicted some novel mutants whose thermostability is possibly elevated, and hopefully these discoveries can be used as guides for our future work on rational design.

Thermal stability and unfolding pathways of Sso7d and its mutant F31A: insight from molecular dynamics simulation.

The thermo-stability and unfolding behaviors of a small hyperthermophilic protein Sso7d as well as its single-point mutation F31A are studied by molecular dynamics simulation at temperatures of 300 K, 371 K and 500 K. Simulations at 300 K show that the F31A mutant displays a much larger flexibility than the wild type, which implies that the mutation obviously decreases the protein's stability. In the simulations at 371 K, although larger fluctuations were observed, both of these two maintain their stable conformations. High temperature simulations at 500 K suggest that the unfolding of these two proteins evolves along different pathways. For the wild-type protein, the C-terminal alpha-helix is melted at the early unfolding stage, whereas it is destroyed much later in the unfolding process of the F31A mutant. The results also show that the mutant unfolds much faster than its parent protein. The deeply buried aromatic cluster in the F31A mutant dissociates quickly relative to the wild-type protein at high temperature. Besides, it is found that the triple-stranded antiparallel ß-sheet in the wild-type protein plays an important role in maintaining the stability of the entire structure.

Uncovering the properties of energy-weighted conformation space networks with a hydrophobic-hydrophilic model.

The conformation spaces generated by short hydrophobic-hydrophilic (HP) lattice chains are mapped to conformation space networks (CSNs). The vertices (nodes) of the network are the conformations and the links are the transitions between them. It has been found that these networks have "small-world" properties without considering the interaction energy of the monomers in the chain, i. e. the hydrophobic or hydrophilic amino acids inside the chain. When the weight based on the interaction energy of the monomers in the chain is added to the CSNs, it is found that the weighted networks show the "scale-free" characteristic. In addition, it reveals that there is a connection between the scale-free property of the weighted CSN and the folding dynamics of the chain by investigating the relationship between the scale-free structure of the weighted CSN and the noted parameter Z score. Moreover, the modular (community) structure of weighted CSNs is also studied. These results are helpful to understand the topological properties of the CSN and the underlying free-energy landscapes.