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@inproceedings{bib_Mini_2025, AUTHOR = {Raghunathan, Aadarsh and Marimuthu, Krishnan }, TITLE = {Minimum Energy Pathway for Lesion Recognition and DNA Binding by RAD4/XPC}, BOOKTITLE = {Journal of Chemical Information and Modeling}. YEAR = {2025}}

The pyrimidine-pyrimidone (6-4) photoproduct (6-4PP) is a UV-induced DNA lesion implicated in skin disorders and cancers. The repair protein XPC/RAD4 detects this lesion and initiates nucleotide excision repair to safeguard genomic integrity. While the X-ray crystallographic structure of the 6–4PP containing DNA-RAD4/XPC complex reveals DNA distortion and extrusion of the lesion and partner bases, the precise mechanism by which RAD4/XPC initiates lesion repair remains unclear. To investigate this, we employed molecular dynamics simulations, umbrella sampling, and the nudged elastic band method to map the minimum energy path (MEP) from RAD4’s initial encounter with damaged DNA to its bound state. Our results reveal that the initial interrogation phase involves partial opening of the DNA, marked by the partial extrusion of the lesion while its partner bases largely remain intrahelical, accompanied by significant DNA unwinding near the damage site. This partially opened state represents the rate-limiting distortion, with 5′ base flipping as the bottleneck for downstream events leading to the bound state. Upon overcoming the bottleneck, the DNA adopts a final untwisted conformation, with the lesion flipping out first, followed by the complete sequential flipping of the 5′ base and then the 3′ partner bases, while full β-hairpin insertion ultimately stabilizes the final bound DNA complex. The energetics and structural intermediates along the MEP provide key insights into conformational changes that drive lesion recognition, extrusion, and stable binding, advancing our understanding of nucleotide excision repair.

@inproceedings{bib_ASH1_2024, AUTHOR = {Yancoskie, Michelle N and Naegeli, Hanspeter and Khaleghi, Reihaneh and G, Anirvinya and Raghunathan, Aadarsh and Gupta, Aryan and Diethelm, Sarah and Maritz, Corina and Sturla, Shana J and Marimuthu, Krishnan }, TITLE = {ASH1L guards cis-regulatory elements against cyclobutane pyrimidine dimer induction}, BOOKTITLE = {Nucleic Acids Research}. YEAR = {2024}}

The histone methyltransferase ASH1L, first discovered for its role in transcription, has been shown to accelerate the removal of ultraviolet (UV) light-induced cyclobutane pyrimidine dimers (CPDs) by nucleotide excision repair. Previous reports demonstrated that CPD excision is most efficient at transcriptional regulatory elements, including enhancers, relative to other genomic sites. Therefore, we analyzed DNA damage maps in ASH1L-proficient and ASH1L-deficient cells to understand how ASH1L controls enhancer stability. This comparison showed that ASH1L protects enhancer sequences against the induction of CPDs besides stimulating repair activity. ASH1L reduces CPD formation at C–containing but not at TT dinucleotides, and no protection occurs against pyrimidine-(6,4)-pyrimidone photoproducts or cisplatin crosslinks. The diminished CPD induction extends to gene promoters but excludes retrotransposons. This guardian role against CPDs in regulatory elements is associated with the presence of H3K4me3 and H3K27ac histone marks, which are known to interact with the PHD and BRD motifs of ASH1L, respectively. Molecular dynamics simulations identified a DNA-binding AT hook of ASH1L that alters the distance and dihedral angle between neighboring C nucleotides to disfavor dimerization. The loss of this protection results in a higher frequency of C–>T transitions at enhancers of skin cancers carrying ASH1L mutations compared to ASH1L-intact counterparts.

@inproceedings{bib_Crit_2023, AUTHOR = {Anirudh, Palutla Narayan and Seth, Shivansh and Ashwin, S.S. and Marimuthu, Krishnan }, TITLE = {Criticality in Alzheimer’s and Healthy Brains: Insights from Phase-Ordering}, BOOKTITLE = {Cognitive Neurodynamics}. YEAR = {2023}}

Criticality, observed during second-order phase transitions, is an emergent phenomenon. The brain operates near criticality where complex systems exhibit high correlations. As a system approaches criticality, it develops “domain”-like regions with competing phases and increased spatio-temporal correlations that diverge. The dynamics of these domains depend on the system’s proximity to criticality. This study explores the differences in the proximity to criticality of Alzheimer’s-afflicted and cognitively normal brains through the use of a spin-lattice model derived from resting-state fMRI data and investigates the type of criticality found in the human brain - whether it is of the Ising class or something more complex. The autocorrelation relaxation time in both groups displays a stretched exponential nature, indicating closer alignment with the criticality of the spin-glass class rather than the Ising class. Longer relaxation times observed in cognitively normal subjects suggest increased proximity to the phase boundary. The weak distinction observed in the spatial characteristics related to proximity to criticality might once more point to a spin-glass scenario, necessitating nuanced order parameters to distinguish between phase-ordering in Alzheimer’s and cognitively normal brains.

@inproceedings{bib_Phas_2023, AUTHOR = {Anirudh, Palutla Narayan and Seth, Shivansh and Ashwin, S. S. and Marimuthu, Krishnan }, TITLE = {Phase ordering in the near-critical regime of the Alzheimer’sand normal brain}, BOOKTITLE = {Technical Report}. YEAR = {2023}}

Criticality, observed during second-order phase transitions, is an emergent phenomenon. The brain operates near criticality, where complex systems exhibit high correlations. The critical brain hypothesis suggests that the brain becomes an efficient learning system in this state but poor in memory, while sub-criticality enhances memory but inhibits learning. As a system approaches criticality, it develops ”domain”-like regions with competing phases and increased spatiotemporal correlations that diverge. The dynamics of these domains depend on the system’s proximity to criticality. This study investigates the phase ordering properties of a spin-lattice model derived from Alzheimer’s and cognitively normal subjects, expecting significant differences in their proximity to criticality. However, our findings show no conclusive distinction in the distal properties from criticality, as reflected in the phase ordering behavior of the Alzheimer’s and cognitively normal brain.

@inproceedings{bib_Mapp_2023, AUTHOR = {Jakhar, Nikhil and SANJEEV, PRABHAKANT AKSHAY and Marimuthu, Krishnan }, TITLE = {Mapping the Recognition Pathway of CyclobutanePyrimidine Dimer in DNA by Rad4/XPC}, BOOKTITLE = {Nucleic Acids Research}. YEAR = {2023}}

UV radiation-induced DNA damages have adverse effects on genome integrity and cellular function. The most prevalent UV-induced DNA lesion is the cyclobutane pyrimidine dimer (CPD), which can cause skin disorders and cancers in humans. Rad4/XPC is a damage sensing protein that recognizes and repairs CPD lesions with high fidelity. However, the molecular mechanism of how Rad4/XPC interrogates CPD lesions remains elusive. Emerging viewpoints indicate that the association of Rad4/XPC with DNA, the insertion of a lesion- sensing β-hairpin of Rad4/XPC into the lesion site, and the flipping of CPD’s partner bases (5’-dA and 3’-dA) are essential for damage recognition. Characterizing these slow events is challenging due to their infrequent occurrence on molecular time scales. Herein, we have used enhanced sampling and molecular dynamics simulations to investigate the mechanism and energetics of lesion recognition by Rad4/XPC, considering multiple plausible pathways between the crystal structure of the Rad4-DNA complex and nine intermediate states. Our results shed light on the most likely sequence of events, their potential coupling and energetics. Upon association, Rad4 and DNA form an encounter complex in which CPD and its partner bases remain in the duplex and the BHD3 β- hairpin is yet to be inserted into the lesion site. Subsequently, sequential base flipping occurs, with the flipping of the 5’-dA base preceding that of the 3’-dA base, followed by the insertion of the BHD3 β-hairpin into the lesion site. The results presented here have significant implications for understanding the molecular basis of UV-related skin disorders and cancers and for paving the way for novel therapeutic strategies. INTRODUCTION DNA plays a central role in the

@inproceedings{bib_Mole_2023, AUTHOR = {Seshadri, Keshavan and Marimuthu, Krishnan }, TITLE = {Molecular Dynamics and Machine Learning Study of Adrenaline Dynamics in the Binding Pocket of GPCR}, BOOKTITLE = {Journal of Chemical Information and Modeling}. YEAR = {2023}}

G-protein coupled receptors (GPCRs) are the most prominent family of membrane proteins that serve as major targets for one-third of the drugs produced. A detailed understanding of the molecular mechanism of drug-induced activation and inhibition of GPCRs is crucial for the rational design of novel therapeutics. The binding of the neurotransmitter adrenaline to the β2-adrenergic receptor (β2AR) is known to induce a flight or fight cellular response, but much remains to be understood about binding-induced dynamical changes in β2AR and adrenaline. In this article, we examine the potential of mean force (PMF) for the unbinding of adrenaline from the orthosteric binding site of β2AR and the associated dynamics using umbrella sampling and molecular dynamics (MD) simulations. The calculated PMF reveals a global energy minimum, which corresponds to the crystal structure of β2AR−adrenaline complex, and a meta-stable state in which the adrenaline is moved slightly deeper into the binding pocket with a different orientation compared to that in the crystal structure. The orientational and conformational changes in adrenaline during the transition between these two states and the underlying driving forces of this transition are also explored. Based on the clustering of MD configurations and machine learning-based statistical analyses of time series of relevant collective variables, the structures and stabilizing interactions of these two states of the β2AR−adrenaline complex are also investigated.

@inproceedings{bib_Mole_2023, AUTHOR = {Seshadri, Keshavan and Marimuthu, Krishnan }, TITLE = {Molecular Dynamics and Machine Learning Study of Adrenaline Dynamics in the Binding Pocket of GPCR}, BOOKTITLE = {Journal of Chemical Information and Modeling}. YEAR = {2023}}

GPCRs are the most prominent family of membrane proteins that serve as major targets for one-third of the drugs produced. A detailed understanding of the molecular mechanism of drug-induced activation and inhibition of GPCRs is crucial for the rational design of novel therapeutics. The binding of the neurotransmitter adrenaline to the β2-adrenergic receptor (β2AR) is known to induce a flight or fight cellular response, but much remains to be understood about binding-induced dynamical changes in β2AR and adrenaline. In this article, we examine the potential of mean force (PMF) for the unbinding of adrenaline from the orthosteric binding site of β2AR and the associated dynamics using umbrella sampling and molecular dynamics (MD) simulations. The calculated PMF reveals a global energy minimum, which corresponds to the crystal structure of β2AR-adrenaline complex, and a metastable state in which the adrenaline is moved slightly deeper into the binding pocket with a different orientation compared to that in the crystal structure. The orientational and conformational changes in adrenaline during the transition between these two states and the underlying driving forces of this transition are also explored. Based on clustering of MD configurations and machine learning-based statistical analyses of time series of relevant collective variables, the structures and stabilizing interactions of these two states of the β2AR-adrenaline complex are also investigated.

@inproceedings{bib_Resp_2022, AUTHOR = {RAJENDRA, VARVDEKAR BHAGYESH and SANJEEV, PRABHAKANT AKSHAY and Marimuthu, Krishnan }, TITLE = {Response of Terahertz Protein Vibrations to Ligand Binding: Calmodulin–Peptide Complexes as a Case Study}, BOOKTITLE = {Journal of Chemical Information and Modeling}. YEAR = {2022}}

Response of Terahertz Protein Vibrations to Ligand Binding: Calmodulin–Peptide Complexes as a Case Study

@inproceedings{bib_CelS_2022, AUTHOR = {Penneru, Sree Kavya and Saharay, Moumita and Marimuthu, Krishnan }, TITLE = {CelS-catalyzed Processive Cellulose Degradation and Cellobiose Extraction for Production of Bioethanol}, BOOKTITLE = {Journal of Chemical Information and Modeling}. YEAR = {2022}}

Bacterial cellulase enzymes are potent candidates for the efficient production of bioethanol, a promising alternative to fossil fuels, from cellulosic biomass. These enzymes catalyze the breakdown of cellulose in plant biomass into simple sugars and then to bioethanol. In the absence of the enzyme, the cellulosic biomass is recalcitrant to decomposition due to fermentationresistant lignin and pectin coatings on the cellulose surface, which make them inaccessible for hydrolysis. Cellobiohydrolase CelS is a microbial enzyme that binds to cellulose fiber and efficiently cleaves it into a simple sugar (cellobiose) by a repeated processive chopping mechanism. The two contributing factors to the catalytic reaction rate and the yield of cellobiose are the efficient product expulsion from the product binding site of CelS and the movement of the substrate or cellulose chain into the active site. Despite progress in understanding product expulsion in other cellulases, much remains to be understood about the molecular mechanism of processive action of these enzymes. Here, nonequilibrium molecular dynamics simulations using suitable reaction coordinates are carried out to investigate the energetics and mechanism of the substrate dynamics and product expulsion in CelS. The calculated free energy barrier for the product expulsion is three times lower than that for the processive action indicating that product removal is relatively easier and faster than the sliding of the substrate to the catalytic active site. The water traffic near the active site in response to the product expulsion and the processive action is also explored.

@inproceedings{bib_Enha_2022, AUTHOR = {Badani, Shaunak Ketan and Marimuthu, Krishnan }, TITLE = {Enhanced Sampling using Replica Exchange with Non-Equilibrium Switches: A Case Study on Simple Models}, BOOKTITLE = {The Journal of Chemical Physics}. YEAR = {2022}}

The configurational sampling is central to characterize the equilibrium properties of complex molecular systems, but it remains a significant computational challenge. The conventional molecular dynamics simulations of limited duration often result in inadequate sampling and thus inaccurate equilibrium estimates. Replica exchange with non-equilibrium switches (RENS) is a collective variable-free computational technique to achieve extensive sampling from a sequence of equilibrium and non-equilibrium MD simulations without modifying the underlying potential energy surface of the system. Unlike the conventional replica exchange molecular dynamics (REMD) simulation, which demands a significant number of replicas for better accuracy, RENS employs non-equilibrium heating (forward) and cooling (reverse) work simulations prior to configurational swaps to improve the acceptance probability for replica exchange. Here, we have implemented the RENS algorithm on four model systems and examined its performance against the conventional MD and REMD simulations. The desired equilibrium distributions were generated by RENS for all the model systems, whereas REMD and MD simulations could not do so due to inadequate sampling on the same timescales. The calculated work distributions from RENS obeyed the expected non-equilibrium fluctuation theorem. The results indicate that the switching time of the non-equilibrium simulations can be systematically altered to optimize the acceptance probability and the reduced work of switching. The modular implementation of RENS algorithm not only enables us to readily extend it to multiple replicas, but also paves the way for extension to larger molecular systems in the future

@inproceedings{bib_Corr_2021, AUTHOR = {T, Rajitha Rajeshwar and Saharay, Moumita and Smith, Jeremy C. and Marimuthu, Krishnan }, TITLE = {Correlated Response of Protein Side-Chain Fluctuations and Conformational Entropy to Ligand Binding}, BOOKTITLE = {The Journal of Physical Chemistry B}. YEAR = {2021}}

The heterogeneous fast side-chain dynamics of proteins plays crucial roles in molecular recognition and binding. Site-specific NMR experiments quantify these motions by measuring the model-free order parameter (Oaxis2) on a scale of 0 (most flexible) to 1 (least flexible) for each methyl-containing residue of proteins. Here, we have examined ligand-induced variations in the fast side-chain dynamics and conformational entropy of calmodulin (CaM) using five different CaM–peptide complexes. Oaxis2 of CaM in the ligand-free (Oaxis,U2) and ligand-bound (Oaxis,B2) states are calculated from molecular dynamics trajectories and conformational energy surfaces obtained using the adaptive biasing force (ABF) method. ΔOaxis2 = Oaxis,B2 – Oaxis,U2 follows a Gaussian-like unimodal distribution whose second moment is a potential indicator of the binding affinity of these complexes. The probability for the binding-induced Oaxis,U2 → Oaxis,B2 transition decreases with increasing magnitude of ΔOaxis2, indicating that large flexibility changes are improbable for side chains of CaM after ligand binding. A linear correlation established between ΔOaxis2 and the conformational entropy change of the protein makes possible the determination of the conformational entropy of binding of protein–ligand complexes. The results not only underscore the functional importance of fast side-chain fluctuations but also highlight key motional and thermodynamic correlates of protein–ligand binding.

@inproceedings{bib_Allo_2020, AUTHOR = {SANJEEV, PRABHAKANT AKSHAY and PANIGRAHI, ABHINANDAN and Marimuthu, Krishnan }, TITLE = {Allosteric Response of DNA Recognition Helices of Catabolite Activator Protein to cAMP and DNA Binding}, BOOKTITLE = {Journal of Chemical Information and Modeling}. YEAR = {2020}}

The homodimeric catabolite activator protein (CAP) regulates the transcription of several bacterial genes based on the cellular concentration of cyclic adenosine monophosphate (cAMP). The binding of cAMP to CAP triggers allosteric communication between the cAMP binding domains (CBD) and DNA binding domains (DBD) of CAP, which entails repositioning of DNA recognition helices (F-helices) in the DBD to dock favorably to the target DNA. Despite considerable progress, much remains to be understood about the mechanistic details of DNA recognition by CAP and about the map of allosteric pathways involved in CAP-mediated gene transcription. The present study uses molecular dynamics and umbrella sampling simulations to investigate the mechanism of cAMP- and DNA-induced changes in the conformation and energetics of F-helices observed during the allosteric regulation of CAP by cAMP and the …

@inproceedings{bib_Sequ_2020, AUTHOR = {Vemuri, Hemanth and PANIGRAHI, ABHINANDAN and Aggarwal, Madhur and KARTHEEK, P and Marimuthu, Krishnan }, TITLE = {Sequence specificity, energetics and mechanism of mismatch recognition by DNA damage sensing protein Rad4/XPC}, BOOKTITLE = {Nucleic Acids Research}. YEAR = {2020}}

The ultraviolet (UV) radiation-induced DNA lesions play a causal role in many prevalent genetic skin-related diseases and cancers. The damage sensing protein Rad4/XPC specifically recognizes and repairs these lesions with high fidelity and safeguards genome integrity. Despite considerable progress, the mechanistic details of the mode of action of Rad4/XPC in damage recognition remain obscure. The present study investigates the mechanism, energetics, dynamics, and the molecular basis for the sequence specificity of mismatch recognition by Rad4/XPC. We dissect the following three key molecular events that occur as Rad4/XPC tries to recognize and bind to DNA lesions/mismatches: (a) the association of Rad4/XPC with the damaged/mismatched DNA, (b) the insertion of a lesion-sensing β-hairpin of Rad4/XPC into the damage/mismatch site and (c) the flipping of a pair of nucleotide bases at the damage/mismatch site. Using suitable reaction coordinates, the free energy surfaces for these events are determined using molecular dynamics (MD) and umbrella sampling simulations on three mismatched (CCC/CCC, TTT/TTT and TAT/TAT mismatches) Rad4-DNA complexes. The study identifies the key determinants of the sequence-dependent specificity of Rad4 for the mismatches and explores the ramifications of specificity in the aforementioned events. The results unravel the molecular basis for the high specificity of Rad4 towards CCC/CCC mismatch and lower specificity for the TAT/TAT mismatch. A strong correlation between the depth of β-hairpin insertion into the DNA duplex and the degree of coupling between the hairpin insertion and the flipping of bases is also observed. The interplay of the conformational flexibility of mismatched bases, the depth of β-hairpin insertion, Rad4-DNA association energetics and the Rad4 specificity explored here complement recent experimental FRET studies on Rad4-DNA complexes.

@inproceedings{bib_Dire_2017, AUTHOR = {RAJESHWAR, T. RAJITHA and Marimuthu, Krishnan }, TITLE = {Direct Determination of Site-specific Noncovalent Interaction Strengths of Proteins from NMR-derived Fast Side Chain Motional Parameters}, BOOKTITLE = {The Journal of Physical Chemistry B}. YEAR = {2017}}

A novel approach to accurately determine residue-specific noncovalent interaction strengths (ξ) of proteins from NMR-measured fast side chain motional parameters (Oaxis2) is presented. By probing the environmental sensitivity of side chain conformational energy surfaces of individual residues of a diverse set of proteins, the microscopic connections between ξ, Oaxis2, conformational entropy (Sconf), conformational barriers, and rotamer stabilities established here are found to be universal among proteins. The results reveal that side chain flexibility and conformational entropy of each residue decrease with increasing ξ and that for each residue type there exists a critical range of ξ, determined primarily by the mean side chain conformational barriers, within which flexibility of any residue can be reversibly tuned from highly flexible (with Oaxis2 ∼ 0) to highly restricted (with Oaxis2 ∼ 1) by increasing ξ by ∼3 kcal …

@inproceedings{bib_Hidd_2014, AUTHOR = {RAJESHWAR, T. RAJITHA and Smith, Jeremy C. and Marimuthu, Krishnan }, TITLE = {Hidden Regularity and Universal Classification of Fast Side Chain Motions in Proteins}, BOOKTITLE = {Journal of the American Chemical Society}. YEAR = {2014}}

Proteins display characteristic dynamical signatures that appear to be universal across all proteins regardless of topology and size. Here, we systematically characterize the universal features of fast side chain motions in proteins by examining the conformational energy surfaces of individual residues obtained using enhanced sampling molecular dynamics simulation (618 free energy surfaces obtained from 0.94 μs MD simulation). The side chain conformational free energy surfaces obtained using the adaptive biasing force (ABF) method for a set of eight proteins with different molecular weights and secondary structures are used to determine the methyl axial NMR order parameters (Oaxis 2), populations of side chain rotamer states (ρ), conformational entropies (Sconf), probability fluxes, and activation energies for side chain interrotameric transitions. The free energy barriers separating side chain rotamer states range from 0.3 to 12 kcal/mol in all proteins and follow a trimodal distribution with an intense peak at∼ 5 kcal/mol and two shoulders at∼ 3 and∼ 7.5 kcal/mol, indicating that some barriers are more favored than others by proteins to maintain a balance between their conformational stability and flexibility. The origin and the influences of the trimodal barrier distribution on the distribution of Oaxis 2 and the side chain conformational entropy are discussed. A hierarchical grading of rotamer states based on the conformational free energy barriers, entropy, and probability flux reveals three distinct classes of side chains in proteins. A unique nonlinear correlation is established between Oaxis 2 and the side chain rotamer populations (ρ). The …

@inproceedings{bib_Thre_2013, AUTHOR = {Glass, Dennis C and Marimuthu, Krishnan and Smith, Jeremy C and Baudry, Jerome }, TITLE = {Three Entropic Classes of Side Chain in a Globular Protein}, BOOKTITLE = {The Journal of Physical Chemistry B}. YEAR = {2013}}

The relationship between the NMR methyl group axial order parameter and the side chain conformational entropy is investigated in inhibitor-bound and apo human HIV protease using molecular dynamics simulation. Three distinct entropic classes of methyl-bearing side chains, determined by the topological distance of the methyl group from the protein backbone (i.e., the number of χ-bonds between the Cα and the carbon of the CH3 group), are revealed by atomistic trajectory analyses performed in the local frame of reference of individual methyl probes. The results demonstrate that topologically equivalent methyl groups experience similar nonbonded microenvironments regardless of the type of residues to which they are attached. Similarly, methyl groups that belong to the same side chain but that are not topologically equivalent exhibit different thermodynamic and dynamic properties. The two-parameter classification (based upon entropy and methyl axial order parameter) of side chains described here permits improved estimates of the conformational entropies of proteins from NMR motional parameters.

@inproceedings{bib_Stru_2013, AUTHOR = {Morrow, C.P. and Yazaydin, A. Özgür and Marimuthu, Krishnan and Bowers, Geoffrey M. and Kalinichev, Andrey G. and Kirkpatrick, R. James }, TITLE = {Structure, energetics, and dynamics of smectite clay hydration: Molecular dynamics investigations of hectorite}, BOOKTITLE = {The Journal of Physical Chemistry C}. YEAR = {2013}}

Toggle navigation CCSD. HAL: HAL; HALSHS; TEL; MédiHAL; Liste des portails; AURéHAL; API; Data; Documentation. Episciences.org: Episciences.org; Revues; Documentation. Sciencesconf.org; Support. Connexion: Connexion; Connexion avec ORCID; se connecter avec Fédération; Créer un compte; Mot de passe oublié ? Login oublié ? fr; en. HAL - hal.archives-ouvertes.fr. Accueil; Déposer; Consulter: par thème arXiv; Par type de document; Les derniers dépôts; par année de publication; par laboratoire; —————; HAL; TEL; INSPIRE-HEP; ArXiv; CDS - CERN. Rechercher. in2p3-01577700, version 1. Structure, energetics, and dynamics of smectite clay hydration: Molecular dynamics investigations of hectorite” (oral). Christin P. Morrow A. Ozgur Yazaydin 1 Marimuthu Krishnan Geoffrey M. Bowers Andrey G. Kalinichev 2 R. James Kirkpatrick Détails. 1 Department of Chemistry. 2 SUBATECH - Laboratoire

@inproceedings{bib_Stru_2012, AUTHOR = {Smith, J.C. and Marimuthu, Krishnan and Petridis, Loukas and Smolin, N. }, TITLE = {Structure and dynamics of biological systems: integration of neutron scattering with computer simulation}, BOOKTITLE = {Dynamics of Soft Matter}. YEAR = {2012}}

The combination of molecular dynamics simulation and neutron scattering techniques has emerged as a highly synergistic approach to elucidate the atomistic details of the structure, dynamics, and functions of biological systems. Simulation models can be tested by calculating neutron scattering structure factors and comparing the results directly with experiments. If the scattering profiles agree, the simulations can be used to provide a detailed decomposition and interpretation of the experiments, and if not, the models can be rationally adjusted. Comparison with neutron experiment can be made at the level of the scattering functions or, less directly, of structural and dynamical quantities derived from them. Here, we examine the combination of simulation and experiment in the interpretation of SANS and inelastic scattering experiments on the structure and dynamics of proteins and other biopolymers.

@inproceedings{bib_Reco_2012, AUTHOR = {Marimuthu, Krishnan and Smith, Jeremy C. }, TITLE = {Reconstruction of Protein Side-Chain Conformational Free Energy Surfaces From NMR-Derived Methyl Axis Order Parameters}, BOOKTITLE = {The Journal of Physical Chemistry B}. YEAR = {2012}}

An analytical approach is developed for reconstructing site-specific methyl-bearing protein side-chain conformational energy surfaces from NMR methyl axis order parameters (Oaxis2). Application of an enhanced sampling algorithm (adaptive biasing force) to molecular dynamics simulation of a protein, calcium-bound calmodulin, reveals a nonlinear correlation between Oaxis2 and the populations of rotamer states of protein side-chains, permitting the rotamer populations to be extracted directly from Oaxis2. The analytical approach yields side-chain conformational distributions that are in excellent agreement with those obtained from the enhanced-sampling MD results.

@inproceedings{bib_Inte_2011, AUTHOR = {Smith, J and Marimuthu, Krishnan and Petridis, Loukas and Smolin, N. }, TITLE = {Integration of neutron scattering with computer simulation to study the structure and dynamics of biological systems}, BOOKTITLE = {Dynamics of Biological Macromolecules by Neutron Scattering}. YEAR = {2011}}

A synergistic approach is described combining computer simulation with experiment in the interpretation of small angle neutron scattering (SANS) and inelastic scattering experiments on the structure and dynamics of proteins and other biopolymers. Simulation models can be tested by calculating neutron scattering structure factors and comparing the results directly with experimental scattering profiles. If the scattering profiles agree the simulations can be used to provide a detailed decomposition and interpretation of the experiments, and if not, the models can be rationally adjusted. Comparison with neutron experiment can be made at the level of the scattering functions or, less directly, of structural and dynamical quantities derived from them. This methodology is discussed in the context of the protein glass transition, protein-solvent dynamical coupling, the density of the hydration shell of proteins and the structural analysis of lignocellulosic biomass.

@inproceedings{bib_Temp_2010, AUTHOR = {Glass, Dennis C. and Marimuthu, Krishnan and Nutt, David R. and Smith, Jeremy C. }, TITLE = {Temperature dependence of protein dynamics simulated with three different water models}, BOOKTITLE = {Journal of Chemical Theory and Computation}. YEAR = {2010}}

The effect of variation of the water model on the temperature dependence of protein and hydration water dynamics is examined by performing molecular dynamics simulations of myoglobin with the TIP3P, TIP4P, and TIP5P water models and the CHARMM protein force field at temperatures between 20 and 300 K. The atomic mean-square displacements, solvent reorientational relaxation times, pair angular correlations between surface water molecules, and time-averaged structures of the protein are all found to be similar, and the protein dynamical transition is described almost indistinguishably for the three water potentials. The results provide evidence that for some purposes changing the water model in protein simulations without a loss of accuracy may be possible.