General formulation of polarizable embedding models and of their coupling

We propose a general formalism for polarizable embedding models that can be applied to either continuum or atomistic polarizable models. After deriving such a formalism for both variational and non-variational models, we address the problem of coupling two polarizable models among themselves and to a quantum mechanical (QM) description in the spirit of multiscale quantum chemistry. We discuss general, model-independent coupling hypotheses and derive coupled polarization equations for all combinations of variational and non-variational models and discuss the embedding contributions to the analytical derivatives of the energy, with a particular focus on the elements of the Fock or Kohn-Sham matrix. We apply the general formalism to the derivation of the working equations for a three-layered, fully polarizable QM/MM/continuum strategy using the non-variational atomic multipole optimized energetics for biomolecular applications polarizable force field and the domain decomposition conductor-like screening model

Successes & challenges in the atomistic modeling of light-harvesting and its photoregulation

Light-harvesting is a crucial step of photosynthesis. Its mechanisms and related energetics have been revealed by a combination of experimental investigations and theoretical modeling. The success of theoretical modeling is largely due to the application of atomistic descriptions combining quantum chemistry, classical models and molecular dynamics techniques. Besides the important achievements obtained so far, a complete and quantitative understanding of how the many different light-harvesting complexes exploit their structural specificity is still missing. Moreover, many questions remain unanswered regarding the mechanisms through which light-harvesting is regulated in response to variable light conditions. Here we show that, in both fields, a major role will be played once more by atomistic descriptions, possibly generalized to tackle the numerous time and space scales on which the regulation takes place: going from the ultrafast electronic excitation of the multichromophoric aggregate, through the subsequent conformational changes in the embedding protein, up to the interaction between proteins

Multiscale Models for Light-Driven Processes

Multiscale models combining quantum mechanical and classical descriptions are a very popular strategy to simulate properties and processes of complex systems. Many alternative formulations have been developed, and they are now available in all of the most widely used quantum chemistry packages. Their application to the study of light-driven processes, however, is more recent, and some methodological and numerical problems have yet to be solved. This is especially the case for the polarizable formulation of these models, the recent advances in which we review here. Specifically, we identify and describe the most important specificities that the polarizable formulation introduces into both the simulation of excited-state dynamics and the modeling of excitation energy and electron transfer processes

The role of charge-transfer states in the spectral tuning of antenna complexes of purple bacteria

The LH2 antenna complexes of purple bacteria occur, depending on light conditions, in various different spectroscopic forms, with a similar structure but different absorption spectra. The differences are related to point changes in the primary amino acid sequence, but the molecular-level relationship between these changes and the resulting spectrum is still not well understood. We undertook a systematic quantum chemical analysis of all the main factors that contribute to the exciton structure, looking at how the environment modulates site energies and couplings in the B800-850 and B800-820 spectroscopic forms of LH2. A multiscale approach combining quantum chemistry and an atomistic classical embedding has been used where mutual polarization effects between the two parts are taken into account. We find that the loss of hydrogen bonds following amino acid changes can only explain a part of the observed blue-shift in the B850 band. The coupling of excitonic states to charge-transfer states, which is different in the two forms, contributes with a similar amount to the overall blue-shift

Genes encoding critical transcriptional activators for murine neural tube development and human spina bifida: a case-control study

<p>Abstract</p> <p>Background</p> <p>Spina bifida is a malformation of the neural tube and is the most common of neural tube defects (NTDs). The etiology of spina bifida is largely unknown, although it is thought to be multi-factorial, involving multiple interacting genes and environmental factors. Mutations in transcriptional co-activator genes-<it>Cited2</it>, <it>p300</it>, <it>Cbp</it>, <it>Tfap2α</it>, <it>Carm1 </it>and <it>Cart1 </it>result in NTDs in murine models, thus prompt us to investigate whether homologues of these genes are associated with NTDs in humans.</p> <p>Methods</p> <p>Data and biological samples from 297 spina bifida cases and 300 controls were derived from a population-based case-control study conducted in California. 37 SNPs within <it>CITED2</it>, <it>EP300</it>, <it>CREBBP</it>, <it>TFAP2A</it>, <it>CARM1 </it>and <it>ALX1 </it>were genotyped using an ABI SNPlex assay. Odds ratios and 95% confidence intervals were calculated for alleles, genotypes and haplotypes to evaluate the risk for spina bifida.</p> <p>Results</p> <p>Several SNPs showed increased or decreased risk, including <it>CITED2 </it>rs1131431 (OR = 5.32, 1.04~27.30), <it>EP300 </it>rs4820428 (OR = 1.30, 1.01~1.67), <it>EP300 </it>rs4820429 (OR = 0.50, 0.26~0.50, in whites, OR = 0.7, 0.49~0.99 in all subjects), <it>EP300 </it>rs17002284 (OR = 0.43, 0.22~0.84), <it>TFAP2A </it>rs3798691 (OR = 1.78, 1.13~2.87 in Hispanics), <it>CREBBP </it>rs129986 (OR = 0.27, 0.11~0.69), <it>CARM1 </it>rs17616105 (OR = 0.41, 0.22~0.72 in whites). In addition, one haplotype block in <it>EP300 </it>and one in <it>TFAP2A </it>appeared to be associated with increased risk.</p> <p>Conclusions</p> <p>Modest associations were observed in <it>CITED2</it>, <it>EP300</it>, <it>CREBBP</it>, <it>TFAP2A </it>and <it>CARM1 </it>but not <it>ALX1</it>. However, these modest associations were not statistically significant after correction for multiple comparisons. Searching for potential functional variants and rare causal mutations is warranted in these genes.</p

Sviluppo di nuovi modelli continui per la descrizione di ambienti dielettrici compositi Development of new continuum models for the description of composite environments

Per introdurre l'effetto dell'ambiente nella descrizione computazionale di proprietà e processi molecolari, si può sfruttare un'approssimazione in cui l'ambiente è descritto come un dielettrico polarizzabile mentre il sistema molecolare di interesse è descritto a livello quantomeccanico. I risultanti modelli continui polarizzabili (PCM) richiedono la risoluzione di un problema elettrostatico che viene effettuata con tecniche numeriche. A questo scopo esistono diverse strategie, di cui le più rilevanti per la chimica computazionale sono: il metodo degli elementi superficiali (BEM) e la più recente tecnica domain decomposition (dd). Il presente lavoro di tesi ha gettato le basi per l'applicazione delle tecniche dd ad ambienti compositi. Il lavoro si è articolato in tre fasi: 1) è stata ultimata l'implementazione del metodo dd già esistente (in grado di descrivere il solo solvente). 2) è stata sviluppata una nuova teoria per la descrizione di sistemi compositi nel framework della domain decomposition. 3) sono stati implementati gli algoritmi relativi al nuovo metodo per combinarlo ad una descrizione quantomeccanica. La prima parte della tesi (capitoli 2 e 3) introduce la teoria dei modelli continui con una dettagliata discussione del problema elettrostatico e delle equazioni integrali ad esso associate. Il capitolo 4 mostra la teoria e le equazioni di lavoro dei metodi che usano la domain decomposition, e in particolare definisce il nuovo metodo per la descrizione dei sistemi compositi. Nel capitolo successivo viene affrontato l'accoppiamento di questi modelli con una descrizione quantistica. Il capitolo 6 descrive l'implementazione all'interno di un codice di calcolo (Gaussian) del metodo sviluppato per solventi semplici e mostra alcuni applicazioni. Infine, il capitolo 7 è interamente dedicato ai sistemi contenenti nanoparticelle metalliche: vengono descritti i principali effetti dovuti al metallo, viene presentata l'implementazione del nuovo metodo e vengono presentate alcune applicazioni. In the computational study of molecular properties and processes, the effect of the environment can be introduced by the means of an approximation which treats the environment as a dielectric polarizable medium while describing the system of interest with a quantum mechanical method. The resulting continuum polarizable models (PCM) require the resolution of an electrostatic problem that is performed with numerical techniques. To this end, there are several strategies, of which the most relevant for computational chemistry are: the surface element method (BEM) and the more recent domain decomposition (dd) technique. The present thesis work has laid the ground for the application of dd techniques to composite environments. The work was divided into three phases: 1) implementation of the already existing dd method (able to describe solvent). 2) developing of a new theory for the description of composite systems in the domain decomposition framework. 3) implementation of the algorithms related to the new method, combining it with a quantum mechanical description. The first part of the thesis (chapters 2 and 3) introduces the PCM theory with a detailed discussion of the electrostatic problem and the related integral equations. Chapter 4 shows the theory and work equations of the domain decomposition methods, and in particular defines the new method for describing composite systems. The following chapter describes the coupling of the method with the quantum description of the solute. Chapter 6 describes the implementation of the dd method for simple solvents and shows some results. Finally, chapter 7 is entirely dedicated to systems containing metal nanoparticles: it describes the main effects due to the metal, the implementation of the new method and shows some results obtained on systems of this type

Fast and Accurate Multilayer Polarizable Embedding Strategies for the Static and Dynamic Modeling of Complex Systems

The computational modeling of molecules embedded in complex (bio)matrices is extremely challenging due to the large dimension of these systems and the complex interactions between the various parts. An effective strategy is resorting to the combination of hybrid quantum/classical models in combination with the use of molecular dynamics techniques, such that the interesting part is described with high accuracy, whereas the rest of the environment is described in a cheap and affordable way. Despite the large diffusion of quantum/classical models, their application to larger and larger systems is still challenging. On one side their implementation often relies on quadratically scaling codes in the number of classical atoms, on the other side the model themselves present intrinsic limitations. In this work, we improved existing quantum/classical implementations both based on molecular mechanics and on polarizable continuum models, such that they can be readily applied to very large systems thanks to a computational cost linear scaling in the classical atoms. Finally, we combined an atomistic model and a polarizable continuum model in a three layer quantum/atomistic/continuum description which takes advantage of the strengths of the two kind of models

Linearly scaling computation of ddPCM solvation energy and forces using the fast multipole method

This paper proposes the first linear scaling implementation for the domain decomposition approach of the polarizable continuum model (ddPCM) for the computation of the solvation energy and forces. The ddPCM-equation consists of a (non-local) integral equation on the van der Waals (vdW) or solvent accessible surface (SAS) of the solute’s cavity resulting in a dense solution matrix and, in turn, one matrix-vector multiplication has a quadratic arithmetic complexity with respect to the number of atoms of the solute molecule. The use of spherical harmonics as basis functions makes it natural to employ the fast multipole method (FMM) in order to provide an asymptotically linear scaling method. In the present paper, we employ the FMM in a non-uniform manner with a clusterization based on a recursive inertial bisection. We present some numerical tests illustrating the accuracy and scaling of our implementation

The molecular mechanisms of light adaption in light-harvesting complexes of purple bacteria revealed by a multiscale modeling

The light-harvesting in photosynthetic purple bacteria can be tuned in response to the light conditions during cell growth. One of the used strategies is to change the energy of the excitons in the major fight-harvesting complex, commonly known as LH2. In the present study we report the first systematic investigation of the microscopic origin of the exciton tuning using three complexes, namely the common (high-light) and the low-light forms of LH2 from Rps. acidophila plus a third complex analogous to the PucD complex from Rps. palustris. The study is based on the combination of classical molecular dynamics of each complex in a lipid membrane and excitonic calculations based on a multiscale quantum mechanics/molecular mechanics approach including a polarizable embedding. From the comparative analysis, it comes out that the mechanisms that govern the adaptation of the complex to different light conditions use the different H-bonding environment around the bacteriochlorophyll pigments to dynamically control both internal and inter-pigment degrees of freedom. While the former have a large effect on the site energies, the latter significantly change the electronic couplings, but only the combination of the two effects can fully reproduce the tuning of the final excitons and explain the observed spectroscopic differences

Polarizable embedding QM/MM: the future gold standard for complex (bio)systems?

Nowadays, hybrid QM/MM approaches are widely used to study (supra)molecular systems embedded in complex biological matrices. However, in their common formulation, mutual interactions between the quantum and classical parts are neglected. To go beyond such a picture, a polarizable embedding can be used. In this perspective, we focus on the induced point dipole formulation of polarizable QM/MM approaches and we show how efficient and linear scaling implementations have allowed their application to the modeling of complex biosystems. In particular, we discuss their use in the prediction of spectroscopies and in molecular dynamics simulations, including Born-Oppenheimer dynamics, enhanced sampling techniques and nonadiabatic descriptions. We finally suggest the theoretical and computational developments that still need to be achieved to overcome the limitations which have prevented so far larger diffusion of these methods