@article{moradi_babin_roland_sagui_2015, title={The Adaptively Biased Molecular Dynamics method revisited: New capabilities and an application}, volume={640}, ISSN={["1742-6596"]}, DOI={10.1088/1742-6596/640/1/012020}, abstractNote={The free energy is perhaps one of the most important quantity required for describing biomolecular systems at equilibrium. Unfortunately, accurate and reliable free energies are notoriously difficult to calculate. To address this issue, we previously developed the Adaptively Biased Molecular Dynamics (ABMD) method for accurate calculation of rugged free energy surfaces (FES). Here, we briefly review the workings of the ABMD method with an emphasis on recent software additions, along with a short summary of a selected ABMD application based on the B-to-Z DNA transition. The ABMD method, along with current extensions, is currently implemented in the AMBER (ver.10-14) software package.}, journal={XXVI IUPAP CONFERENCE ON COMPUTATIONAL PHYSICS (CCP2014)}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2015} }
 @article{babin_wang_rose_sagui_2013, title={Binding Polymorphism in the DNA Bound State of the Pdx1 Homeodomain}, volume={9}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1003160}, abstractNote={The subtle effects of DNA-protein recognition are illustrated in the homeodomain fold. This is one of several small DNA binding motifs that, in spite of limited DNA binding specificity, adopts crucial, specific roles when incorporated in a transcription factor. The homeodomain is composed of a 3-helix domain and a mobile N-terminal arm. Helix 3 (the recognition helix) interacts with the DNA bases through the major groove, while the N-terminal arm becomes ordered upon binding a specific sequence through the minor groove. Although many structural studies have characterized the DNA binding properties of homeodomains, the factors behind the binding specificity are still difficult to elucidate. A crystal structure of the Pdx1 homeodomain bound to DNA (PDB 2H1K) obtained previously in our lab shows two complexes with differences in the conformation of the N-terminal arm, major groove contacts, and backbone contacts, raising new questions about the DNA recognition process by homeodomains. Here, we carry out fully atomistic Molecular Dynamics simulations both in crystal and aqueous environments in order to elucidate the nature of the difference in binding contacts. The crystal simulations reproduce the X-ray experimental structures well. In the absence of crystal packing constraints, the differences between the two complexes increase during the solution simulations. Thus, the conformational differences are not an artifact of crystal packing. In solution, the homeodomain with a disordered N-terminal arm repositions to a partially specific orientation. Both the crystal and aqueous simulations support the existence of different stable binding conformers identified in the original crystallographic data with different degrees of specificity. We propose that protein-protein and protein-DNA interactions favor a subset of the possible conformations. This flexibility in DNA binding may facilitate multiple functions for the same transcription factor.}, number={8}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={Babin, Volodymyr and Wang, Dongli and Rose, Robert B. and Sagui, Celeste}, year={2013}, month={Aug} }
 @article{moradi_babin_roland_sagui_2010, title={A classical molecular dynamics investigation of the free energy and structure of short polyproline conformers}, volume={133}, ISSN={["0021-9606"]}, DOI={10.1063/1.3481087}, abstractNote={Folded polyproline peptides can exist as either left-(PPII) or right-handed (PPI) helices, depending on their environment. In this work, we have characterized the conformations and the free energy landscapes of Ace–(Pro)n–Nme, n=2,3,…,9, and 13 peptides both in vacuo and in an implicit solvent environment. In order to enhance the sampling provided by regular molecular dynamics simulations, we have used the recently developed adaptively biased molecular dynamics method—which provides an accurate description of the free energy landscapes in terms of a set of relevant collective variables—combined with Hamiltonian and temperature replica exchange molecular dynamics methods. The collective variables, which are chosen so as to reflect the stable structures and the “slow modes” of the polyproline system, were based primarily on properties of length and of the cis/trans isomerization associated with the prolyl bonds. Results indicate that the space of peptide structures is characterized not just by pure PPII and PPI structures, but rather by a broad distribution of stable minima with similar free energies. These results are in agreement with recent experimental work. In addition, we have used steered molecular dynamics methods in order to quantitatively estimate the free energy difference of PPI and PPII for peptides of the length n=2,…,5 in vacuo and implicit water and qualitatively investigate transition pathways and mechanisms for the PPII to PPI transitions. A zipper-like mechanism, starting from either the center of the peptide or the amidated end, appear to be the most likely mechanisms for the PPII→PPI transition for the longer peptides.}, number={12}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2010}, month={Sep} }
 @article{babin_sagui_2010, title={Conformational free energies of methyl-alpha-L-iduronic and methyl-beta-D-glucuronic acids in water}, volume={132}, ISSN={["1089-7690"]}, DOI={10.1063/1.3355621}, abstractNote={We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a non-equilibrium umbrella sampling method, in this case the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the WHAM technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of $\alpha$-L-iduronic acid and its C5 epimer $\beta$-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.}, number={10}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Babin, Volodymyr and Sagui, Celeste}, year={2010}, month={Mar} }
 @article{moradi_lee_babin_roland_sagui_2010, title={Free energy and structure of polyproline peptides: An ab initio and classical molecular dynamics investigation}, volume={110}, number={15}, journal={International Journal of Quantum Chemistry}, author={Moradi, M. and Lee, J. G. and Babin, V. and Roland, C. and Sagui, C.}, year={2010}, pages={2865–2879} }
 @article{babin_karpusenka_moradi_roland_sagui_2009, title={Adaptively Biased Molecular Dynamics: An Umbrella Sampling Method With a Time-Dependent Potential}, volume={109}, ISSN={["1097-461X"]}, DOI={10.1002/qua.22413}, abstractNote={We discuss an adaptively biased molecular dynamics (ABMD) method for the computation of a free energy surface for a set of reaction coordinates. The ABMD method belongs to the general category of umbrella sampling methods with an evolving biasing potential. It is characterized by a small number of control parameters and an O(t) numerical cost with simulation time t. The method naturally allows for extensions based on multiple walkers and replica exchange mechanism. The workings of the method are illustrated with a number of examples, including sugar puckering, and free energy landscapes for polymethionine and polyproline peptides, and for a short β-turn peptide. ABMD has been implemented into the latest version (Case et al., AMBER 10; University of California: San Francisco, 2008) of the AMBER software package and is freely available to the simulation community. © 2009 Wiley Periodicals, Inc. Int J Quantum Chem, 2009}, number={15}, journal={INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY}, author={Babin, Volodymyr and Karpusenka, Vadzim and Moradi, Mahmoud and Roland, Christopher and Sagui, Celeste}, year={2009}, month={Dec}, pages={3666–3678} }
 @article{moradi_babin_roland_darden_sagui_2009, title={Conformations and free energy landscapes of polyproline peptides}, volume={106}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.0906500106}, abstractNote={The structure of the proline amino acid allows folded polyproline peptides to exist as both left- (PPII) and right-handed (PPI) helices. We have characterized the free energy landscapes of hexamer, nanomer, and tridecamer polyproline peptides in gas phase and implicit water as well as explicit hexane and 1-propanol for the nanomer. To enhance the sampling provided by regular molecular dynamics, we used the recently developed adaptively biased molecular dynamics method, which describes Landau free energy maps in terms of relevant collective variables. These maps, as a function of the collective variables of handedness, radius of gyration, and three others based on the peptide torsion angle ω, were used to determine the relative stability of the different structures, along with an estimate of the transition pathways connecting the different minima. Results show the existence of several metastable isomers and therefore provide a complementary view to experimental conclusions based on photo-induced electron transfer experiments with regard to the existence of stable heterogeneous subpopulations in PPII polyproline.}, number={49}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Darden, Thomas A. and Sagui, Celeste}, year={2009}, month={Dec}, pages={20746–20751} }
 @article{babin_roland_sagui_2008, title={Adaptively biased molecular dynamics for free energy calculations}, volume={128}, DOI={10.1063/1.2844595}, abstractNote={We present an adaptively biased molecular dynamics (ABMD) method for the computation of the free energy surface of a reaction coordinate using nonequilibrium dynamics. The ABMD method belongs to the general category of umbrella sampling methods with an evolving biasing potential and is inspired by the metadynamics method. The ABMD method has several useful features, including a small number of control parameters and an O(t) numerical cost with molecular dynamics time t. The ABMD method naturally allows for extensions based on multiple walkers and replica exchange, where different replicas can have different temperatures and/or collective variables. This is beneficial not only in terms of the speed and accuracy of a calculation, but also in terms of the amount of useful information that may be obtained from a given simulation. The workings of the ABMD method are illustrated via a study of the folding of the Ace-GGPGGG-Nme peptide in a gaseous and solvated environment.}, number={13}, journal={Journal of Chemical Physics}, author={Babin, V. and Roland, C. and Sagui, C.}, year={2008} }
 @article{lee_asciutto_babin_sagui_darden_roland_2006, title={Deprotonation of solvated formic acid: Car-Parrinello and metadynamics simulations}, volume={110}, ISSN={["1520-5207"]}, DOI={10.1021/jp055809i}, abstractNote={The deprotonation of solvated formic acid was investigated theoretically with ab initio simulations. With the Car−Parrinello method, deprotonation and reprotonation by means of a proton wire were observed. The microscopics of these reactions were analyzed, and reveal the key role played by nearby water molecules in catalyzing the reactions. A constrained molecular dynamics calculation was carried out to estimate the dissociation free energy. Deprotonation of formic acid was further investigated with the recently developed metadynamics method using the formic acid oxygen coordination numbers as the collective variables. The determined free-energy landscape gives barriers similar to that obtained with the constrained free-energy calculation.}, number={5}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Lee, JG and Asciutto, E and Babin, V and Sagui, C and Darden, T and Roland, C}, year={2006}, month={Feb}, pages={2325–2331} }
 @article{babin_baucom_darden_sagui_2006, title={Molecular dynamics simulations of DNA with polarizable force fields: Convergence of an ideal B-DNA structure to the crystallographic structure}, volume={110}, ISSN={["1520-5207"]}, DOI={10.1021/jp061421r}, abstractNote={We have investigated to what extent molecular dynamics (MD) simulations can reproduce DNA sequence-specific features, given different electrostatic descriptions and different cell environments. For this purpose, we have carried out multiple unrestrained MD simulations of the DNA duplex d(CCAACGTTGG)2. With respect to the electrostatic descriptions, two different force fields are studied: a traditional description based on atomic point charges and a polarizable force field. With respect to the cell environment, the difference between crystal and solution environments is emphasized, as well as the structural importance of divalent ions. By imposing the correct experimental unit cell environment, an initial configuration with two ideal B-DNA duplexes in the unit cell is shown to converge to the crystallographic structure. This convergence is measured by the appearance of sequence-dependent features that very closely resemble the crystallographic ones as well as by the decay of the all-atom root-mean-squared coordinates deviations (RMSD) with respect to the crystallographic structure. Given the appropriate crystallographic constraints, this is the first example of multiple nanosecond molecular dynamics trajectory that shows an ideal B-DNA model converging to an experimental structure, with a significant decay of RMSD.}, number={23}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Babin, Volodymyr and Baucom, Jason and Darden, Thomas A. and Sagui, Celeste}, year={2006}, month={Jun}, pages={11571–11581} }
 @article{babin_baucom_darden_sagui_2006, title={Molecular dynamics simulations of polarizable DNA in crystal environment}, volume={106}, ISSN={0020-7608 1097-461X}, url={http://dx.doi.org/10.1002/qua.21152}, DOI={10.1002/qua.21152}, abstractNote={Abstract We have investigated the role of the electrostatic description and cell environment in molecular dynamics (MD) simulations of DNA. Multiple unrestrained MD simulations of the DNA duplex d(CCAACGTTGG) 2 have been carried out using two different force fields: a traditional description based on atomic point charges and a polarizable force field. For the time scales probed, and given the “right” distribution of divalent ions, the latter performs better than the nonpolarizable force field. In particular, by imposing the experimental unit cell environment, an initial configuration with ideal B‐DNA duplexes in the unit cell acquires sequence‐dependent features that very closely resemble the crystallographic ones. Simultaneously, the all‐atom root‐mean‐square coordinates deviation (RMSD) with respect to the crystallographic structure is seen to decay. At later times, the polarizable force field is able to maintain this lower RMSD, while the nonpolarizable force field starts to drift away. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2006}, number={15}, journal={International Journal of Quantum Chemistry}, publisher={Wiley}, author={Babin, Volodymyr and Baucom, Jason and Darden, Thomas A. and Sagui, Celeste}, year={2006}, pages={3260–3269} }
 @article{babin_roland_darden_sagui_2006, title={The free energy landscape of small peptides as obtained from metadynamics with umbrella sampling corrections}, volume={125}, ISSN={["1089-7690"]}, DOI={10.1063/1.2393236}, abstractNote={There is considerable interest in developing methodologies for the accurate evaluation of free energies, especially in the context of biomolecular simulations. Here, we report on a reexamination of the recently developed metadynamics method, which is explicitly designed to probe "rare events" and areas of phase space that are typically difficult to access with a molecular dynamics simulation. Specifically, we show that the accuracy of the free energy landscape calculated with the metadynamics method may be considerably improved when combined with umbrella sampling techniques. As test cases, we have studied the folding free energy landscape of two prototypical peptides: Ace-(Gly)(2)-Pro-(Gly)(3)-Nme in vacuo and trialanine solvated by both implicit and explicit water. The method has been implemented in the classical biomolecular code AMBER and is to be distributed in the next scheduled release of the code.}, number={20}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Babin, Volodymyr and Roland, Christopher and Darden, Thomas A. and Sagui, Celeste}, year={2006}, month={Nov} }