Molecular dynamics simulations have been performed to compute the solvation free energy and octanol/water partition coefficients for a challenging set of selected organic molecules, characterized by simultaneous presence functional groups coarsely spanning large portion chemical space in druglike compounds and, many cases, complex conformational landscape (2-propoxyethanol, acetylsalicylic acid, cyclohexanamine, dialifor, ketoprofen, nitralin, profluralin, terbacil). OPLS-AA GAFF2...

The potential of mean force interacting aromatic amino acids is calculated using molecular dynamics simulations. free energy surface determined in order to study stacking and T-shape competition for phenylalanine−phenylalanine (Phe−Phe), phenylalanine−tyrosine (Phe−Tyr), tyrosine−tyrosine (Tyr−Tyr) complexes vacuo, water, carbon tetrachloride, methanol. Stacked structures are favored all solvents with the exception Tyr−Tyr complex where T-shaped also important. effect anchoring two α-carbons...

EXTENDED ABSTRACT ENEA is the Italian National Agency for New Technologies, Energy and Sustainable Economic Development. operates in many sectors among which most important are: energy technologies, materials physics, life sciences climate. In framework of its institutional mission, ICT Division provides computing storage resources integrated into ENEAGRID/CRESCO, an infrastructure distributed over 6 sites, whose main facilities are HPC CRESCO clusters. The bulk all based on IBM Spectrum...

In this study, we present a new molecular dynamics program for simulation of complex systems. The program, named ORAC, combines state-of-the-art (MD) algorithms with flexibility in handling different types and sizes molecules. ORAC is intended simulations systems specifically designed to treat biomolecules efficiently effectively solution or crystalline environment. Among its unique features are: (i) implementation reversible symplectic multiple time step (or r-RESPA, reference system...

An analysis of the conformational properties and hydrogen bonding in condensed phases glycerol is reported using same model as adopted Part I (Phys. Chem. Phys., 1999, 1, 871). Structural liquid glassy states are analyzed relation to molecular backbone conformation molecule. The effects temperature on distribution analyzed. structural dynamical also investigated. results consistent with available experimental observations clarify many important interrelated aspects microscopic structure...

We propose a new approach for the umbrella sampling method in molecular dynamics simulations of complex systems. An accelerated slow degrees freedom is achieved by generating single self-adaptive trajectory that tends to span uniformly reaction coordinate using time dependent bias potential derived from preceding history system. To show convergent behavior and efficiency method, we present free energy surface alanine dipeptide water as function backbone dihedral angles.

A polarizable electrostatic potential model for classical molecular mechanics is presented. Based on the chemical equalization (CPE) principle, developed starting from original formulation of Mortier, Ghosh, and Shankar [J. Am. Chem. Soc. 108, 4315 (1986)]. Following York Yang Phys. 104, 159 (1996)] we present an SP-basis CPE parametrization to describe realistically any sort system. By fitting ab initio electronic properties, such as dipole moment, polarizability global hardness a...

Using a model potential function we have performed molecular dynamics simulation of several static and dynamical properties glycerol in the crystal, glass liquid phases. Comparison with available experimental data shows an excellent agreeent proves validity used. For calculation molar specific heat developed theoretical approach which takes into account contributions conformational structure energy vibrational computed using Bose–Einstein statistics.

In this paper we compare the polarization response given by two different chemical potential equalization schemes to be applied molecular dynamics simulations: standard fluctuating point charge model (FQ) and atom–atom transfer (AACT). We have tested transferability of FQ AACT parameters, fitted polarizability small size alkanes polyenes, large homologues. show that scheme is not adequate for n-alkanes as it strongly overestimates tensor components number carbon atoms increases. The approach...

Long range electrostatic forces are involved at a fundamental level in many biological phenomena. Their prohibitive computational costs often prevents their correct calculation molecular dynamics (MD) simulations of molecules. In this paper we present method to handle efficiently and exactly interactions MD with periodic boundary conditions. Our scheme employs multiple time step r-RESPA integration algorithm combination the Ewald summation technique, is specifically targeted simulation large...

Constant pressure and temperature algorithms have been derived based on a reversible multiple time step (r-RESPA) approach new modification of the particle mesh Ewald method. As such they provide very fast accurate tools for simulation complex molecular systems in ensembles other than microcanonical. We also developed novel scaling scheme named atomic group which is similar to scaling, but has important computational advantages when used conjunction with bond constraints. The investigation...

In the present study we have used molecular dynamics simulations to stability of antiparallel β-sheet in cellular mouse prion protein (PrPC) and D178N mutant. particular, using recently developed non-Markovian metadynamics method, evaluated free energy as a function reaction coordinate related disruption/growth. We found that is significantly weaker pathogenic mutant than wild-type PrPC. The destabilization PrPC β-structure correlated weakening hydrogen bonding network involving mutated...

We present the new release of ORAC engine (Procacci et al., Comput Chem 1997, 18, 1834), a FORTRAN suite to simulate complex biosystems at atomistic level. The previous code included multiple time steps integration, smooth particle mesh Ewald method, constant pressure and temperature simulations. has been supplemented with most advanced techniques for enhanced sampling in systems including replica exchange solute tempering, metadynamics steered molecular dynamics. All these computational...

Using a database of 6166 experimental structures taken from the Protein Data Bank, we have studied pair interactions between planar residues (Phe, Tyr, His, Arg, Glu and Asp) in proteins, known as π–π interactions. On basis appropriate coordinates defining mutual arrangement two residues, calculated 2-D potentials mean force aimed at determining stability most probable for aromatic–aromatic, aromatic–cation aromatic–anion bound pairs. Our analysis reveals thermodynamic relevance ubiquity...

The present paper is intended to be a comprehensive assessment and rationalization, from statistical mechanics perspective, of existing alchemical theories for binding free energy calculations ligand–receptor systems. In detail, the foundation noncovalent interactions in systems revisited, providing unifying treatment that encompasses most important variants approaches seminal double annihilation method [Jorgensen et al. J. Chem. Phys. 1988; 89, 3742] decoupling [Gilson Biophys. 1997; 72,...

We present PrimaDORAC, a simple and freely accessible web interface for generating the topology parameter files of organic or drug molecules to be used in molecular mechanics dynamics calculations. The relies on our in-house FORTRAN90 parser, working recently released Generalized Amber Force Field set (GAFF2). AM1/BCC charges are computed using Public Domain MOPAC7 program bond charge corrections (BCC) reported Jakalian, A.; Jack, D. B.; Bayly, C. I.; J. Comp. Chem., 2002, 23, 1623-1641. has...

We developed and validated a novel force field in the context of AMBER parameterization for simulation zinc(II)-binding proteins. The proposed assumes nonbonded spherical interactions between central zinc(II) coordinating residues. A crucial innovative aspect our approach is to account polarization effects cation by redefining atomic charges residues an adjustment Lennard-Jones parameters Zn-interacting atoms reproduce mean distance distributions. optimal transferable parametrization was...

We present a new release (6.0β) of the ORAC program [Marsili et al. J. Comput. Chem. 2010, 31, 1106-1116] with hybrid OpenMP/MPI (open multiprocessing message passing interface) multilevel parallelism tailored for generalized ensemble (GE) and fast switching double annihilation (FS-DAM) nonequilibrium technology aimed at evaluating binding free energy in drug-receptor system on high performance computing platforms. The production GE or FS-DAM trajectories is handled using weak scaling...

In the context of drug–receptor binding affinity calculations using molecular dynamics techniques, we implemented a combination Hamiltonian replica exchange (HREM) and novel nonequilibrium alchemical methodology, called virtual double-system single-box, with increased accuracy, precision, efficiency respect to standard approaches. The method has been applied for determination absolute free energies 16 newly designed noncovalent ligands main protease (3CLpro) SARS-CoV-2. core structures...

We present our blind predictions for the Statistical Assessment of Modeling Proteins and Ligands (SAMPL), ninth challenge, focusing on binding WP6 (carboxy-pillar[6]arene) with ammonium/diammonium cationic guests. Host-guest free energies have been calculated using recently developed virtual double system single box approach, based enhanced sampling bound unbound end-states followed by fast switching nonequilibrium alchemical simulations [M. Macchiagodena et al., J. Chem. Theory Comput. 16,...

In this paper we describe the implementation of a very fast molecular dynamic method to realistically handle electrostatic interactions in simulations solvated proteins. Our scheme is based on recently proposed reversible multiple time step (r-RESPA) algorithm and new modification particle mesh Ewald method. While latter technique provides accurate representation Coulombic for infinite systems, r-RESPA exploits separation force into components with increasingly longer scales corresponding...