Massimo Marchi

ORAC: A Molecular dynamics program to simulate complex molecular systems with realistic electrostatic interactions

In this study, we present a new molecular dynamics program for simulation of complex molecular systems. The program, named ORAC, combines state‐of‐the‐art molecular dynamics (MD) algorithms with flexibility in handling different types and sizes of molecules. ORAC is intended for simulations of molecular systems and is specifically designed to treat biomolecules efficiently and effectively in solution or in a crystalline environment. Among its unique features are: (i) implementation of reversible and symplectic multiple time step algorithms (or r‐RESPA, reversible reference system propagation algorithm) specifically designed and tuned for biological systems with periodic boundary conditions; (ii) availability for simulations with multiple or single time steps of standard Ewald or smooth particle mesh Ewald (SPME) for computation of electrostatic interactions; and (iii) possibility of simulating molecular systems in a variety of thermodynamic ensembles. We believe that the combination of these algorithms makes ORAC more advanced than other MD programs using standard simulation algorithms. © 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1848–1862, 1997

COORDINATES SCALING AND MULTIPLE TIME STEP ALGORITHMS FOR SIMULATION OF SOLVATED PROTEINS IN THE NPT ENSEMBLE

Constant pressure and temperature algorithms have been derived based on a reversible multiple time step (r-RESPA) approach and a new modification of the particle mesh Ewald method. As such they provide very fast and accurate tools for simulation of complex molecular systems in ensembles other than the microcanonical. We have also developed a novel scaling scheme named atomic group scaling which is similar to atomic scaling, but has important computational advantages when used in conjunction with bond constraints. The investigation of the molecular and atomic group scaling schemes against static and dynamic properties of a test system (a solvated bovine pancreatic trypsin inhibitor) has confirmed their equivalence also for large molecules such as proteins. For the specific test system the simulation box cell volume upon changes of pressure decays to its equilibrium value within 5 ps of simulation for both approaches. This goes against theoretical arguments that molecular scaling would not be suitable for s...

Adiabatic bias molecular dynamics: A method to navigate the conformational space of complex molecular systems

This study deals with a novel molecular simulation technique, named adiabatic bias molecular dynamics (MD), which provides a simple and reasonably inexpensive route to generate MD trajectories joining points in conformational space separated by activation barriers. Because of the judicious way the biasing potential is updated during the MD runs, the technique allows with some additional effort the computation of the free energy change experienced during the trajectory. The adiabatic bias method has been applied to a nontrivial problem: The unfolding of an atomistic model of lysozyme. Here, the radius of gyration (Rg) was used as a convenient reaction coordinate. For changes in Rg between 19.7 and 28 A, we observe a net loss of the native tertiary structure of lysozyme. At the same time, secondary structure elements such as α-helices are retained although some of the original order is diminished. The calculated free energy profile for the unfolding transition shows a monotonous increase with Rg and depends...

Molecular Simulations of Dodecyl-β-maltoside Micelles in Water: Influence of the Headgroup Conformation and Force field Parameters

This paper deals with the development and validation of new potential parameter sets, based on the CHARMM36 and GLYCAM06 force fields, to simulate micelles of the two anomeric forms (α and β) of N-dodecyl-β-maltoside (C(12)G(2)), a surfactant widely used in the extraction and purification of membrane proteins. In this context, properties such as size, shape, internal structure, and hydration of the C(12)G(2) anomer micelles were thoroughly investigated by molecular dynamics simulations and the results compared with experiments. Additional simulations were also performed with the older CHARMM22 force field for carbohydrates (Kuttel, M.; et al. J. Comput. Chem. 2002, 23, 1236-1243). We find that our CHARMM and GLYCAM parameter sets yield similar results in the case of properties related to the micelle structure but differ for other properties such as the headgroup conformation or the micelle hydration. In agreement with experiments, our results show that for all model potentials the β-C(12)G(2) micelles have a more pronounced ellipsoidal shape than those containing α anomers. The computed radius of gyration is 20.2 and 25.4 Å for the α- and β-anomer micelles, respectively. Finally, we show that depending on the potential the water translational diffusion of the interfacial water is 7-11.5 times slower than that of bulk water due to the entrapment of the water in the micelle crevices. This retardation is independent of the headgroup in α- or β-anomers.

A dielectric continuum molecular dynamics method

We introduce a novel method to simulate hydrated macromolecules with a dielectric continuum representation of the surrounding solvent. In our approach, the interaction between the solvent and the molecular degrees of freedom is described by means of a polarization density free energy functional which is minimum at electrostatic equilibrium. After a pseudospectral expansion of the polarization and a discretization of the functional, we construct the equations of motion for the system based on a Car–Parrinello technique. In the limit of the adiabatic evolution of the polarization field variables, our method provides the solution of the dielectric continuum problem “on the fly,” while the molecular coordinates are propagated. In this first study, we show how our dielectric continuum molecular dynamics method can be successfully applied to hydrated biomolecules, with low cost compared to free energy simulations with explicit solvent. To our knowledge, this is the first time that stable and conservative molecu...

Electrostatic calculations and multiple time scales in molecular dynamics simulation of flexible molecular systems

In this paper, we deal with the handling of the electrostatic forces in complex molecular systems. In particular, we focus on instabilities experienced by reversible multiple time step algorithms when used in conjunction with Ewald summation techniques for periodic systems. We show that energy conservation is negatively affected by the intra-molecular energy term due to electrostatic excluded contacts required by the most frequently used of the modern force fields for biomolecular systems. These effects are due to a non-complete cancellation of the intra-molecular electrostatic energy and forces at intermediate or long time steps.

Expressing our internal states and understanding those of others

Significance Vitality form is a term that describes the manner with which actions are performed. Despite their crucial importance in interpersonal communication, vitality forms have been almost completely neglected in neuroscience. Here, using a functional MRI technique, we investigated the neural correlates of vitality forms in three tasks: action observation, imagination, and execution. We found that, in all three tasks, there is a common specific activation of the dorsocentral sector of the insula in addition to the parietofrontal network that is typically active during arm movements production and observation. Thus, the dorsocentral part of the insula seems to represent a fundamental and previously unsuspected node that modulates the cortical motor circuits, allowing individuals to express their vitality forms and understand those of others. Vitality form is a term that describes the style with which motor actions are performed (e.g., rude, gentle, etc.). They represent one characterizing element of conscious and unconscious bodily communication. Despite their importance in interpersonal behavior, vitality forms have been, until now, virtually neglected in neuroscience. Here, using the functional MRI (fMRI) technique, we investigated the neural correlates of vitality forms in three different tasks: action observation, imagination, and execution. Conjunction analysis showed that, in all three tasks, there is a common, consistent activation of the dorsocentral sector of the insula. In addition, a common activation of the parietofrontal network, typically active during arm movements production, planning, and observation, was also found. We conclude that the dorsocentral part of the insula is a key element of the system that modulates the cortical motor activity, allowing individuals to express their internal states through action vitality forms. Recent monkey anatomical data show that the dorsocentral sector of the insula is, indeed, connected with the cortical circuit involved in the control of arm movements.

Increased Functional Connectivity in the Default Mode Network in Mild Cognitive Impairment: A Maladaptive Compensatory Mechanism Associated with Poor Semantic Memory Performance

Semantic memory decline and changes of default mode network (DMN) connectivity have been reported in mild cognitive impairment (MCI). Only a few studies, however, have investigated the role of changes of activity in the DMN on semantic memory in this clinical condition. The present study aimed to investigate more extensively the relationship between semantic memory impairment and DMN intrinsic connectivity in MCI. Twenty-one MCI patients and 21 healthy elderly controls matched for demographic variables took part in this study. All participants underwent a comprehensive semantic battery including tasks of category fluency, visual naming and naming from definition for objects, actions and famous people, word-association for early and late acquired words and reading. A subgroup of the original sample (16 MCI patients and 20 healthy elderly controls) was also scanned with resting state functional magnetic resonance imaging and DMN connectivity was estimated using a seed-based approach. Compared with healthy elderly, patients showed an extensive semantic memory decline in category fluency, visual naming, naming from definition, words-association, and reading tasks. Patients presented increased DMN connectivity between the medial prefrontal regions and the posterior cingulate and between the posterior cingulate and the parahippocampus and anterior hippocampus. MCI patients also showed a significant negative correlation of medial prefrontal gyrus connectivity with parahippocampus and posterior hippocampus and visual naming performance. Our findings suggest that increasing DMN connectivity may contribute to semantic memory deficits in MCI, specifically in visual naming. Increased DMN connectivity with posterior cingulate and medio-temporal regions seems to represent a maladaptive reorganization of brain functions in MCI, which detrimentally contributes to cognitive impairment in this clinical population.

Electrostatics on particles: Phenomenological and orientational density functional theory approach

In order to describe efficiently the solvation of complex solutes in computer simulations, we introduce several simple particle-based models with the requirement that they yield, on average, either an exact or approximate representation of the macroscopic laws of electrostatics. First, in a phenomenological approach, electrostatics of continuous media is formulated in terms of a polarization density free energy functional, which is projected on randomly distributed discrete Lennard-Jones pseudoparticles. The resulting model is that a polarizable fluid, in which the induced dipoles describe both orientational and electronic polarization. The problem of the connection between the macroscopic dielectric constant and the pseudoparticles polarizability is examined and important deviations with respect to the commonly accepted Clausius–Mossotti relation are found. Dipolar saturation effects can also be added to the model to yield a “nonlocal Langevin solvent model” and an approximate, numerically very efficient...

Modeling the Self-Aggregation of Small AOT Reverse Micelles from First-Principles

This Letter is the first attempt at studying the self-aggregation of AOT reverse micelles from first-principles. It focuses on predicting the aggregation number, the radius of gyration, and the hydrodynamic radius of a low water content reverse micelle by theoretical means. We show that molecular dynamics simulation in the μs time range combined with atomistic potentials is capable of reproducing and explaining, to a convenient degree, experimental results on the size and dimensions of reverse micelles of AOT of low water content, [H2O]/[AOT] ≈ 5.