Solvent Accessible Surface Area Calculations Research Articles

Unraveling the enigma: Probing the unconventional binding site and binding mechanism of entrectinib with human serum albumin through spectroscopic, molecular docking, and dynamic simulation analyses

Entrectinib (ENB), a novel potent tyrosine kinase inhibitor, has demonstrated promising activity against specific genetic alterations in various solid tumors. Investigating the interaction of ENB with human serum albumin (HSA) provides valuable insights into its binding characteristics and pharmacological behavior. The interaction between ENB and HSA was investigated using various spectroscopic techniques, molecular docking, and simulations approaches. Fluorescence spectroscopy revealed a consistent decrease in the intrinsic fluorescence of HSA upon binding to ENB, indicating a static binding mechanism. The binding constant calculated from Stern Volmer and double-log equations (KSV) and (K) were determined to be 4.11 x104 M−1 and 4.38 x104 M−1, respectively at 298 K, indicating moderate binding affinity. Thermodynamic analysis demonstrated a spontaneous interaction (ΔG < 0) with an enthalpy change (ΔH) of −5.59 kJ mol−1 and an entropy change (ΔS) of + 70.36 J mol−1 K−1, indicating that the interaction is primarily driven by electrostatic forces with potential involvement of hydrogen bonding. Synchronous and 3D fluorescence analysis indicated no significant changes in the microenvironment surrounding Tyr and Trp residues upon ENB binding. Near and far UV spectrophotometric analyses confirmed the formation of the ENB-HSA complex and suggested no conformational changes in the protein structure. Fluorescence measurements and binding competition analysis using site markers revealed that ENB selectively binds to the HSA Sudlow sites I and III, displacing phenylbutazone at both sites. Molecular docking studies confirmed the binding of ENB to Sudlow sites I and III and identified critical residues involved in the interaction. Molecular dynamics simulations further validated the stability of the ENB-HSA complex at both sites, with more favorable binding at site III, and minimal fluctuations observed in the root mean square deviation, root mean square fluctuation, and radius of gyration. Hydrogen bond analysis and solvent accessible surface area calculations supported the strong binding and accessibility of ENB within the HSA structure. Overall, the experimental and computational results provided valuable insights into the ENB-HSA interaction, elucidating the binding mechanism and key residues involved.

Structure and Conformational Properties of a Short Polyaniline Chain in a Mixture of Water and Ionic Liquid [1-Ethyl-3-methyl-imidazolium][bistriflimide] Investigated by All-Atom Molecular Dynamics Simulations.

Development of antifouling membranes for water treatment using conducting polymers and their composites is a fundamental strategy to mitigate the fouling. This manuscript presents an all-atom molecular dynamics simulations of a conducting polymer, polyaniline (PANI), immersed in an ionic liquids (ILs)-water mixtures. We have considered the ionic liquid 1-ethyl-3-methyl imidazolium bistriflimide, [EMIM]+[BIS]-. The two forms of polyaniline, emeraldine base (EB) and emeraldine salt (ES), were considered. Various intra- and intermolecular structural properties of PANI were analyzed, such as polymer chain radius of gyration Rg, radial distribution functions, and torsional angle distributions. The Rg of EB shows an increase, while the Rg of ES shows a decrease with an increase in the IL concentration. The backbone torsional angle probability distributions show a significant trans state for EB, while a combination of trans and gauche states was observed for ES. Similar supportive distributions were seen in the backbone angular distributions. Radial distribution functions between the carbon atoms at ortho and meta positions of the benzene ring on both ES and EB, as well as the amine group attached between two benzene rings, show an enhanced interaction with the ionic liquid compared to water. Anions have a dominant interaction with the polymer chain when compared to cations. The solvent accessible surface area (SASA) calculations were in accordance with the EB and ES structural properties. The SASA values are more favorable for ES than for EB. H-bond analysis shows a decrease in the number of H-bonds with water as the IL concentration increases.

Inhibitory action of indanone-carbamate hybrid molecules on the aggregation of Aβ16−22 peptides and their translocation across POPC lipid bilayer

The aggregation of Aβ peptides leads to Alzheimer's Disease (AD), the most common kind of dementia. This neurodegenerative disease has no permanent cure to date. Drug design for Alzheimer's is, therefore, a major challenge to the scientific community. A recent experimental study showed the potency of two indanone-carbamate-based molecules to act as drugs against AD. However, the central molecular mechanism of action of these inhibitors is unknown. For knowing the mechanism of amyloid aggregation and the role of these novel molecules as inhibitors, an extensive all-atom molecular dynamics simulation of the Aβ16−22 peptides is performed. A variety of analyses are carried out to explore the structural change of the peptides in an aqueous medium in the absence and presence of inhibitors viz. secondary structure analysis, solvent accessible surface area calculation, residue-wise and Cα atom-wise contact mapping. In order to identify the peptide's residues associated with amyloid aggregation and interaction with the inhibitor, nonbonding interaction energies, radial distribution functions, coordination number, hydrogen bonds, and potential of mean forces are estimated. The central hydrophobic core, more importantly, the aromatic phenylalanine residues are found to play a substantial role in the formation of toxic amyloid oligomers. All the analyses demonstrate diminishing interpeptide interactions in presence of the inhibitors thereby checking amyloid aggregation. The molecules are also found to destabilize preformed amyloid fibrils. Furthermore, permeation properties of these small molecule inhibitors are investigated across a model POPC lipid bilayer, revealing their biocompatibility and translocation mechanisms.

Bioinformatics-Guided Expansion and Discovery of Graspetides.

Graspetides are a class of ribosomally synthesized and post-translationally modified peptide natural products featuring ATP-grasp ligase-dependent formation of macrolactones/macrolactams. These modifications arise from serine, threonine, or lysine donor residues linked to aspartate or glutamate acceptor residues. Characterized graspetides include serine protease inhibitors such as the microviridins and plesiocin. Here, we report an update to Rapid ORF Description and Evaluation Online (RODEO) for the automated detection of graspetides, which identified 3,923 high-confidence graspetide biosynthetic gene clusters. Sequence and co-occurrence analyses doubled the number of graspetide groups from 12 to 24, defined based on core consensus sequence and putative secondary modification. Bioinformatic analyses of the ATP-grasp ligase superfamily suggest that extant graspetide synthetases diverged once from an ancestral ATP-grasp ligase and later evolved to introduce a variety of ring connectivities. Furthermore, we characterized thatisin and iso-thatisin, two graspetides related by conformational stereoisomerism from Lysobacter antibioticus. Derived from a newly identified graspetide group, thatisin and iso-thatisin feature two interlocking macrolactones with identical ring connectivity, as determined by a combination of tandem mass spectrometry (MS/MS), methanolytic, and mutational analyses. NMR spectroscopy of thatisin revealed a cis conformation for a key proline residue, while molecular dynamics simulations, solvent-accessible surface area calculations, and partial methanolytic analysis coupled with MS/MS support a trans conformation for iso-thatisin at the same position. Overall, this work provides a comprehensive overview of the graspetide landscape, and the improved RODEO algorithm will accelerate future graspetide discoveries by enabling open-access analysis of existing and emerging genomes.

Accurate Estimation of Solvent Accessible Surface Area for Coarse-Grained Biomolecular Structures with Deep Learning.

Coarse-grained (CG) models of biomolecules have been widely used in protein/ribonucleic acid (RNA) three-dimensional structure prediction, docking, drug design, and molecular simulations due to their superiority in computational efficiency. Most of these applications strongly depend on the reasonable estimation of solvation free energy, which requires the accurate calculation of solvent accessible surface area (SASA). Although algorithms for SASA calculations with all-atom protein and RNA structures have been well-established, accurately estimating the SASA based on CG structures is extremely challenging. In this work, we developed a deep learning-based SASA estimator (DeepCGSA), which can provide almost perfect SASA estimation based on CG structures of protein and RNA molecules. Extensive testing analysis showed that for three types of widely used CG protein models, including the Cα-based, Cα-Cβ, and Martini models, the correlation coefficients between the predicted values and the reference values can be as high as 0.95-0.99, which perform dramatically better than available methods. In addition, the new method can be used for CG RNA structures and unfolded protein structures with much improved accuracy. We anticipate that DeepCGSA will be highly useful in the protein/RNA structure prediction, drug design, and other applications, in which accurate estimations of SASA for CG biomolecular structures are critically important.

Electrostatic Self-Assembly Approach to Fabricate Architectures of Carboxyl Functionalized Gold-Aryl Nanoparticles and Graphene Oxide Platforms

Graphene oxide (GO) was decorated with gold-aryl (Au-C) nanoparticles AuNPs-COOH by sodium borohydride reduction of aryldiazonium tetrachloroaurate(III) salt at room temperature in aqueous solutions. Brunauer-Emmett-Teller measurements supported GO anchoring by AuNPs modified with COOH; surface area dropped significantly. Morphology of AuNPs-COOH/GO nanocomposite (NC) was probed using AFM and TEM, showing NC’s surface roughness and wrinkling. XPS results suggest the clear reductive reaction of tetrachloroaurate anion into metallic gold in AuNPs-COOH/GO along with detailed interpretations of functional groups’ nature. Molecular dynamics calculations endowed support of favorable wrinkling at the edges and carboxyl intercalation to GO surface of types π- π, hydrogen bonding, and hydrophobic interactions. Solvent accessible surface area calculations of GO showed a decrease in total surface area. Environmental nanoremediation of the catalytic reduction of 4-nitrophenol, a priority pollutant listed by USEPA, was investigated. The apparent rate constants Kapp of four catalytic reduction cycles of nitrophenol were measured. The highest value is 1.17 × 10-1 min-1 for the first cycle which decreased to 4.49 × 10 -2 min -1 for the fourth cycle. The variations in rate constants were measured with different conditions, including NaBH 4 concentrations, NC loadings and NC incubating time in NaBH4.

Calculation of accurate interatomic contact surface areas for the quantitative analysis of non-bonded molecular interactions.

SummaryIntra- and intermolecular contact surfaces are routinely calculated for a large array of applications in bioinformatics but are typically approximated from differential solvent accessible surface area calculations and not calculated directly. These approximations do not properly take the effects of neighboring atoms into account and tend to deviate considerably from the true contact surface. We implemented an extension of the original Shrake-Rupley algorithm to accurately estimate interatomic contact surface areas of molecular structures and complexes. Our extended algorithm is able to calculate the contact area of an atom to all nearby atoms by directly calculating overlapping surface patches, taking into account the possible shielding effects of neighboring atoms. Here, we present a versatile software tool and web server for the calculation of contact surface areas, as well as buried surface areas and solvent accessible surface areas (SASA) for different types of biomolecules, such as proteins, nucleic acids and small organic molecules. Detailed results are provided in tab-separated values format for analysis and Protein Databank files for visualization. Direct contact surface area calculation resulted in improved accuracy in a benchmark with a non-redundant set of 245 protein–DNA complexes. SASA-based approximations underestimated protein–DNA contact surfaces on average by 40%. This software tool may be useful for surface-based intra- and intermolecular interaction analyses and scoring function development.Availability and implementationA web server, stand-alone binaries for Linux, MacOS and Windows and C++ source code are freely available from http://schuellerlab.org/dr_sasa/.Supplementary information Supplementary data are available at Bioinformatics online.

Using molecular dynamics simulations to identify the key factors responsible for chiral recognition by an amino acid-based molecular micelle

Molecular dynamics (MD) simulations were used to investigate the binding of six chiral compounds to the amino acid-based molecular micelle (MM) poly-(sodium undecyl-(L)-leucine-leucine) or poly(SULL). The MM investigated is used as a chiral selector in capillary electrophoresis. The project goal was to characterize the chiral recognition mechanism in these separations and to move toward predictive models to identify the best amino acid-based MM for a given separation. Poly(SULL) was found to contain six binding sites into which chiral compounds could insert. Four sites had similar sizes, shapes, and electrostatic properties. Enantiomers of alprenolol, propranolol, 1,1′-bi-2-naphthyl-2,2′-diyl hydrogen phosphate, 1,1′-bi-2-naphthol, chlorthalidone, or lorazepam were separately docked into each binding pocket and MD simulations with the resulting intermolecular complexes were performed. Solvent-accessible surface area calculations showed the compounds preferentially associated with binding sites where they penetrated into the MM core and shielded their non-polar atoms from solvent. Furthermore, with five of the six compounds the enantiomer with the most favorable free energy of MM association also experienced the most favorable intermolecular hydrogen bonding interactions with the MM. This result suggests that stereoselective intermolecular hydrogen bonds play an important role in chiral discrimination in separations using amino acid-based MMs.GRAPHICAL ABSTRACT

Molecular dynamics simulation analysis of Focal Adhesive Kinase (FAK) docked with solanesol as an anti-cancer agent.

Focal adhesion kinase (FAK) plays a primary role in regulating the activity of many signaling molecules. Increased FAK expression has been associated in a series of cellular processes like cell migration and survival. FAK inhibition by an anti cancer agent is critical. Therefore, it is of interest to identify, modify, design, improve and develop molecules to inhibit FAK. Solanesol is known to have inhibitory activity towards FAK. However, the molecular principles of its binding with FAK is unknown. Solanesol is a highly flexible ligand (25 rotatable bonds). Hence, ligand-protein docking was completed using AutoDock with a modified contact based scoring function. The FAK-solanesol complex model was further energy minimized and simulated in GROMOS96 (53a6) force field followed by post simulation analysis such as Root mean square deviation (RMSD), root mean square fluctuations (RMSF) and solvent accessible surface area (SASA) calculations to explain solanesol-FAK binding.

Binding mode prediction and MD/MMPBSA-based free energy ranking for agonists of REV-ERBα/NCoR.

The knowledge of the free energy of binding of small molecules to a macromolecular target is crucial in drug design as is the ability to predict the functional consequences of binding. We highlight how a molecular dynamics (MD)-based approach can be used to predict the free energy of small molecules, and to provide priorities for the synthesis and the validation via in vitro tests. Here, we study the dynamics and energetics of the nuclear receptor REV-ERBα with its co-repressor NCoR and 35 novel agonists. Our in silico approach combines molecular docking, molecular dynamics (MD), solvent-accessible surface area (SASA) and molecular mechanics poisson boltzmann surface area (MMPBSA) calculations. While docking yielded initial hints on the binding modes, their stability was assessed by MD. The SASA calculations revealed that the presence of the ligand led to a higher exposure of hydrophobic REV-ERB residues for NCoR recruitment. MMPBSA was very successful in ranking ligands by potency in a retrospective and prospective manner. Particularly, the prospective MMPBSA ranking-based validations for four compounds, three predicted to be active and one weakly active, were confirmed experimentally.

Structure-Based Correlation of Light-Induced Histidine Reactivity in A Model Protein.

Light is known to induce covalently linked aggregates in proteins. These aggregates can be immunogenic and are of concern for drug product development in the biotechnology industry. Histidine (His) is proposed to be a key residue in cross-link generation ( Pattison , D. I. Photochem. Photobiol. Sci. 2012 , 11 , 38 - 53 ). However, the factors that influence the reactivity of His in proteins, especially the intrinsic factors are little known. Here, we used rhDNase, which only forms His-His covalent dimers after light treatment to determine the factors that influence the light-induced reactivity of His. This system allowed us to fully characterize the light-induced covalent dimer and rank the reactivities of the His residues in this protein. The reactivities of these His residues were correlated with solvent accessibility-related parameters both by crystal structure-based calculations of solvent-accessible surface area and by hydrogen-deuterium exchange (HDX) experiments. Through this correlation, we demonstrate that the photoreactivity of His is determined by both solvent accessibility and structural flexibility. This new insight can explain the highly complex chemistry of light-induced aggregation and help predict the aggregation propensity of protein under light treatment.

Binding Free Energy and the structural changes determination in hGH protein with different concentrations of copper ions (A molecular dynamics simulation study)

In this study, we estimated the optimum concentration of copper ions that are effective in the stability and the structural changes of human growth hormone (hGH) protein in the combination of different concentrations of these ions at the molecular level using molecular dynamics simulation by Gromacs 4.6.5 software. Moreover, to estimate the binding affinity of copper ions to hGH protein, binding free energies is calculated by the molecular mechanics Poisson–Boltzmann Surface Area (MM-PBSA). The analysis of molecular dynamics (MD) trajectories as dictionary of the secondary structure of protein (DSSP), solvent accessible surface area (SASA) and binding free energy calculations show that hGH protein structure is more stabilized by increasing a limited concentration of copper ions. These findings align with our previous experimental studies.

Molecular Simulations of Solved Co-crystallized X-Ray Structures Identify Action Mechanisms of PDEδ Inhibitors

PDEδ is a small protein that binds and controls the trafficking of RAS subfamily proteins. Its inhibition protects initiation of RAS signaling, and it is one of the common targets considered for oncological drug development. In this study, we used solved x-ray structures of inhibitor-bound PDEδ targets to investigate mechanisms of action of six independent all-atom MD simulations. An analysis of atomic simulations combined with the molecular mechanic-Poisson-Boltzmann solvent accessible surface area/generalized Born solvent accessible surface area calculations led to the identification of action mechanisms for a panel of novel PDEδ inhibitors. To the best of our knowledge, this study is one of the first in silico investigations on co-crystallized PDEδ protein. A detailed atomic-scale understanding of the molecular mechanism of PDEδ inhibition may assist in the design of novel PDEδ inhibitors. One of the most common side effects for diverse small molecules/kinase inhibitors is their off-target interactions with cardiac ion channels and human-ether-a-go-go channel specifically. Thus, all of the studied PDEδ inhibitors are also screened in silico at the central cavities of hERG1 potassium channels.

Structural significance of modified nucleoside 5-taurinomethyl-2-thiouridine, τm5s2U, found at ‘wobble’ position in anticodon loop of human mitochondrial tRNALys

The myoclonus epilepsy associated with ragged-red fibers (MERRF) is a mitochondrial encephalomyopathic disease caused due to the lack of hypermodified nucleoside 5-taurinomethyl-2-thiouridine at ‘wobble’ 34th position in the anticodon loop of human mitochondrial tRNALys. Understanding the structural significance of τm5s2U might be helpful to get more information about the MERRF disease in detail at the atomic level. Hence, conformational preferences of hypermodified nucleoside 5-taurinomethyl-2-thiouridine 5′-monophosphate, ‘p-τm5s2U,’ have been studied using semiempirical quantum chemical RM1 method. Full geometry optimization using ab initio molecular orbital HF-SCF (6-31G**) and DFT (B3LYP/6-31G**) methods has also been used to compare the salient features. The RM1 preferred most stable conformation of ‘p-τm5s2U’ has been stabilized by hydrogen bonding interactions between O(11a)…HN(8), O1P(34)…HN(8), O1P(34)…HC(10), O4′(34)…HC(6), S(2)…HC1′(34), O5′(34)…HC(6), and O(4)…HC(7). Another conformational study of 5-taurinomethyl-2-thiouridine side chain in the presence of anticodon loop bases of human mitochondrial tRNALys showed similar conformation as found in RM1 preferred most stable conformation of ‘p-τm5s2U.’ The glycosyl torsion angle of τm5s2U retains ‘anti’ conformation. Similarly, MD simulation results are also found in accordance with RM1 preferred stable structure. The solvent-accessible surface area calculations revealed surface accessibility of τm5s2U in human mt tRNALys anticodon loop. The MEPs calculations of codon–anticodon models of τm5s2U(34):G3 and τm5s2U(34):A3 showed unique potential tunnels between the hydrogen bond donor and acceptor atoms. These results might be useful to understand the exact role of τm5s2U(34) to recognize AAG/AAA codons and to design new strategies to prevent mitochondrial disease, MERRF.

Conformational Preferences of Modified Nucleoside 5-Taurinomethyluridine, τm(5)U Occur at 'wobble' 34th Position in the Anticodon Loop of tRNA.

Conformational preferences of hypermodified nucleoside 5-taurinomethyluridine 5'-monophoshate 'p-τm(5)U' (-CH2-NH2(+)-CH2-CH2-SO3(-)) have been investigated using semi-empirical RM1 method. Automated geometry optimization using ab initio molecular orbital HF-SCF (6-31G**) and DFT (B3LYP/6-31G**) calculations have also been made to compare the salient features. The RM1 preferred most stable conformation of 'p-τm(5)U' has been stabilized by hydrogen bonding interactions between O(11a)…HN(8), O1P(34)…HN(8), and O1P(34)…HC(10). Another conformational study of 5-taurinomethyluridine side chain has also been performed in context of anticodon loop bases of E. coli tRNA(Leu). The atom O(11a) of τm(5)U(34) side chain interacts with adenosine (A35) as well as ribose-phosphate backbone which might provide structural stability to the anticodon loop. The glycosyl torsion angle of τm(5)U retains 'anti'-conformation. The solvent accessible surface area calculations revealed the role of τm(5)U in tRNA(Leu) anticodon loop. MD simulation results are found in agreement with RM1 preferred stable structure. The MEPs calculations of τm(5)U(34):G3 model show unique potential tunnels between the hydrogen bond donor and acceptor atoms as compared to τm(5)U(34):A3 model. Thus, these results could pave the way to understand the role of τm(5)U(34) to recognize UUG/UUA codons at atomic level in the mitochondrial disease, MELAS.

TRIFORCE: Tessellated Semianalytical Solvent Exposed Surface Areas and Derivatives.

We present a new approach to the calculation of solvent-accessible surface areas of molecules with potential application to surface area based methods for determination of solvation free energies. As in traditional analytical and statistical approaches, this new algorithm, called TRIFORCE, reports both component areas and derivatives as a function of the atomic coordinates and radii. Unique to TRIFORCE are the rapid and scalable approaches for the determination of sphere intersection points and numerical estimation of the surface areas, derivatives, and other properties that can be associated with the surface area facets. The algorithm performs a special tessellation and semianalytical integration that uses a precomputed look-up table. This provides a simple way to balance numerical accuracy and memory usage. TRIFORCE calculates derivatives in the same manner, enabling application in force-dependent activities such as molecular geometry minimization. TRIFORCE is available free of charge for academic purposes as both a C++ library, which can be directly interfaced to existing molecular simulation packages, and a web-accessible application.

A Review of Methods Available to Estimate Solvent-Accessible Surface Areas of Soluble Proteins in the Folded and Unfolded States

Solvent accessible surface area (SASA) of proteins has always been considered as a decisive factor in protein folding and stability studies. It is defined as the surface characterized around a protein by a hypothetical centre of a solvent sphere with the van der Waals contact surface of the molecule. Based on SASA values, amino acid residues of a protein can be classified as buried or exposed. There are various types of SASAs starting from relative solvent accessibility to absolute surface areas. Direct estimation of accurate SASAs of folded proteins experimentally at the atomic level is not possible. However, the SASA of a native protein can be estimated computationally from the atomic coordinates. Similarly, various simulation methods are available to compute the SASA of a protein in its unfolded state. In efforts to estimate the changes in SASA related to the protein folding, a number of the unfolded state models have been proposed. In this review, we have summarized different algorithms and computational tools for SASA estimations. Furthermore, online resources for SASA calculations and representations have also been discussed in detail. This review will be useful for protein chemists and biologists for the accurate measurements of SASA and its subsequent applications for the calculation of various biophysical and thermodynamic properties of proteins.

Hydration of porphyrin and Mg–porphyrin: ab initio quantum mechanical charge field molecular dynamics simulations

Ab initio QMCF-MD simulations were performed for porphyrin (POR) and magnesium-porphyrin (Mg-POR) immersed in water to study their structural and dynamical properties. The observed hydration behaviour of these solutes representing biomimetic models is in fair agreement with structural and dynamical features of their biological analogues, protoporphyrin IX (PPIX) and chlorophyll (CHl). Structural data obtained from the radial, angular and spatial distribution functions as well as the angular-radial distributions have a consensus on possessing a contrasting hydration behaviour of POR and Mg-POR. Flexibility of the ring in both solutes described by the improper torsional distribution and root mean square fluctuation showed an influence on H-bond interactions between the nitrogen atoms and water molecules that are also reflected in the respective dynamics. An axial water molecule coordinated to the Mg(ii) ion indicates the penta-coordinated Mg-POR to be stable along the simulation. It was also shown that complexation of the Mg(ii) ion to the porphyrin influences the hydration patterns significantly compared to the porphyrin itself, which is further supported by the vibrational power spectra evaluated for both solutes. Free energy of binding and solvent accessible surface area calculations also confirmed that these two solutes have distinct hydration behaviour. Detailed knowledge of the individual hydration patterns is expected to be of particular benefit.

Accelerated Conformational Entropy Calculations Using Graphic Processing Units

Conformational entropy calculation, usually computed by normal-mode analysis (NMA) or quasi harmonic analysis (QHA), is extremely time-consuming. Here, instead of NMA or QHA, a solvent accessible surface area (SASA) based model was employed to compute the conformational entropy, and a new fast GPU-based method called MURCIA (Molecular Unburied Rapid Calculation of Individual Areas) was implemented to accelerate the calculation of SASA for each atom. MURCIA employs two different kernels to determine the neighbors of each atom. The first kernel (K1) uses brute force for the calculation of the neighbors of atoms, while the second one (K2) uses an advanced algorithm involving hardware interpolations via GPU texture memory unit for such purpose. These two kernels yield very similar results. Each kernel has its own advantages depending on the protein size. K1 performs better than K2 when the size is small and vice versa. The algorithm was extensively evaluated for four protein data sets and achieves good results for all of them. This GPU-accelerated version is ∼600 times faster than the former sequential algorithm when the number of the atoms in a protein is up to 10⁵.

Conformational Preferences of Modified Nucleoside N(4)-Acetylcytidine, ac4C Occur at “Wobble” 34th Position in the Anticodon Loop of tRNA

Conformational preferences of modified nucleoside, N(4)-acetylcytidine, ac(4)C have been investigated using quantum chemical semi-empirical RM1 method. Automated geometry optimization using PM3 method along with ab initio methods HF SCF (6-31G**), and density functional theory (DFT; B3LYP/6-31G**) have also been made to compare the salient features. The most stable conformation of N(4)-acetyl group of ac(4)C prefers "proximal" orientation. This conformation is stabilized by intramolecular hydrogen bonding between O(7)···HC(5), O(2)···HC2', and O4'···HC(6). The "proximal" conformation of N(4)-acetyl group has also been observed in another conformational study of anticodon loop of E. coli elongator tRNA(Met). The solvent accessible surface area (SASA) calculations revealed the role of ac(4)C in anticodon loop. The explicit molecular dynamics simulation study also shows the "proximal" orientation of N(4)-acetyl group. The predicted "proximal" conformation would allow ac(4)C to interact with third base of codon AUG/AUA whereas the 'distal' orientation of N(4)-acetyl cytidine side-chain prevents such interactions. Single point energy calculation studies of various models of anticodon-codon bases revealed that the models ac(4)C(34)(Proximal):G3, and ac(4)C(34)(Proximal):A3 are energetically more stable as compared to models ac(4)C(34)(Distal):G3, and ac(4)C(34)(Distal):A3, respectively. MEPs calculations showed the unique potential tunnels between the hydrogen bond donor-acceptor atoms of ac(4)C(34)(Proximal):G3/A3 base pairs suggesting role of ac(4)C in recognition of third letter of codons AUG/AUA. The "distal" conformation of ac(4)C might prevent misreading of AUA codon. Hence, this study could be useful to understand the role of ac(4)C in the tertiary structure folding of tRNA as well as in the proper recognition of codons during protein biosynthesis process.