Milan Hodoscek

CHARMM: The biomolecular simulation program

CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates, and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model‐building capabilities. The CHARMM program is applicable to problems involving a much broader class of many‐particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical‐molecular mechanical force fields, to all‐atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This article provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM article in 1983.

Interfacing Q-Chem and CHARMM to perform QM/MM reaction path calculations†

A hybrid quantum mechanical/molecular mechanical (QM/MM) potential energy function with Hartree‐Fock, density functional theory (DFT), and post‐HF (RIMP2, MP2, CCSD) capability has been implemented in the CHARMM and Q‐Chem software packages. In addition, we have modified CHARMM and Q‐Chem to take advantage of the newly introduced replica path and the nudged elastic band methods, which are powerful techniques for studying reaction pathways in a highly parallel (i.e., parallel/parallel) fashion, with each pathway point being distributed to a different node of a large cluster. To test our implementation, a series of systems were studied and comparisons were made to both full QM calculations and previous QM/MM studies and experiments. For instance, the differences between HF, DFT, MP2, and CCSD QM/MM calculations of H2O···H2O, H2O···Na+, and H2O···Cl− complexes have been explored. Furthermore, the recently implemented polarizable Drude water model was used to make comparisons to the popular TIP3P and TIP4P water models for doing QM/MM calculations. We have also computed the energetic profile of the chorismate mutase catalyzed Claisen rearrangement at various QM/MM levels of theory and have compared the results with previous studies. Our best estimate for the activation energy is 8.20 kcal/mol and for the reaction energy is −23.1 kcal/mol, both calculated at the MP2/6‐31+G(d)//MP2/6‐31+G(d)/C22 level of theory.

Optimization of quantum mechanical molecular mechanical partitioning schemes: Gaussian delocalization of molecular mechanical charges and the double link atom method

Two new techniques for modeling chemical processes in condensed phases with combined quantum mechanical and molecular mechanical (QM/MM) potentials are introduced and tested on small, model compounds. The first technique, the double link atom (DLA) method, is an extension of the traditional, single link atom (SLA) method to avoid some of the problems with the latter method. These problems are primarily electrostatic, as the SLA method can produce an unphysical overall charge or dipole. The second technique, the delocalized Gaussian MM charge (DGMM) method, is an empirical way to include the delocalized character of the electron density of atoms in the MM region. This can be important for the electrostatic interaction of the QM region with nearby atoms in the MM region, and it can simplify the rules governing which classical interactions are included in the energies and forces. Even for very short distances, the DGMM method does not require the neglect of the MM host in the QM calculation. The DGMM method ...

CHARMMing: A new, flexible, web portal for CHARMM

A new web portal for the CHARMM macromolecular modeling package, CHARMMing (CHARMM interface and graphics, http://www.charmming.org), is presented. This tool provides a user-friendly interface for the preparation, submission, monitoring, and visualization of molecular simulations (i.e., energy minimization, solvation, and dynamics). The infrastructure used to implement the web application is described. Two additional programs have been developed and integrated with CHARMMing: GENRTF, which is employed to define structural features not supported by the standard CHARMM force field, and a job broker, which is used to provide a portable method for using grid and cluster computing with CHARMMing. The use of the program is described with three proteins: 1YJP , 1O1O , and 1UFY . Source code is provided allowing CHARMMing to be downloaded, installed, and used by supercomputing centers and research groups that have a CHARMM license. Although no software can replace a scientists own judgment and experience, CHARMMing eases the introduction of newcomers to the molecular modeling discipline by providing a graphical method for running simulations.

Catalytic mechanism of aldose reductase studied by the combined potentials of quantum mechanics and molecular mechanics

The catalytic reduction of D-glyceraldehyde to glycerol by aldose reductase has been investigated with the combined potentials of quantum mechanics (QM) and molecular mechanics (MM) to resolve the question of whether Tyr48 or His110 serves as the proton donor during catalysis. Site directed mutagenesis studies favor Tyr48 as the proton donor while the presence of a water channel linking the N delta 1 of His110 to the bulk solvent suggests that His110 is the proton donor. Utilizing the combined potentials of QM and MM, the binding mode of substrate D-glyceraldehyde was investigated by optimizing the local geometry of Asp43, Lys77, Tyr48, His110 and NADPH at the active site of aldose reductase. Reaction pathways for the reduction of D-glyceraldehyde to glycerol were then constructed by treating both Tyr48 and His110 as proton donors. Comparison of energetics obtained from the reaction pathways suggests His110 to be the proton donor. Based on these findings, a reduction mechanism of D-glyceraldehyde to glycerol is described.

Targeted molecular dynamics simulation studies of binding and conformational changes in E. coli MurD.

Enzymes involved in the biosynthesis of bacterial peptidoglycan, an essential cell wall polymer unique to prokaryotic cells, represent a highly interesting target for antibacterial drug design. Structural studies of E. coli MurD, a three‐domain ATP hydrolysis driven muramyl ligase revealed two inactive open conformations of the enzyme with a distinct C‐terminal domain position. It was hypothesized that the rigid body rotation of this domain brings the enzyme to its closed active conformation, a structure, which was also determined experimentally. Targeted molecular dynamics 1 ns‐length simulations were performed in order to examine the substrate binding process and gain insight into structural changes in the enzyme that occur during the conformational transitions into the active conformation. The key interactions essential for the conformational transitions and substrate binding were identified. The results of such studies provide an important step toward more powerful exploitation of experimental protein structures in structure‐based inhibitor design. Proteins 2007.

Mills-nixon effect in benzocyclobutenes

Abstract The structural features of benzocyclobutenes were studied using several semiempirical and ab initio techniques. Qualitative hybridization arguments and actual 6–31 G Hartree-Fock calculations show conclusively that benzocyclobutenes exhibit a typical Mills-Nixon effect which is most pronounced in benzo[1,2:3,4:5,6]tricyclobutene. It is concluded that the experimental X-ray structure of the perfluoro derivative of the latter compound is seriously in error.

Introduction of solvent effects in the electrostatic recognition of biological receptors

Abstract Molecular electrostatic potentials of a molecule K , immersed in a solvent but in close contact with a bulky molecular system, have been computed at different levels of approximation to derive a new molecular index of the propensity of K to be bound to appropriate chemical groups of the bulky system (e.g. the substrate—receptor interaction in biochemical reactions). This index differs from the usual molecular electrostatic potential computed in vacuo, because it takes into account the effect of the solvent (after the partial desolvation due to the intimate contact with the bulky system) and, if desired, the effect of the electrostatic interaction with the bulky system itself.

Strong Mills-Nixon effect in biphenylene

Abstract Structural features of biphenylene are studied by semiempirical and ab initio SCF methods employing STO-3G, 3-21G and 6-31G basis sets. The latter gives results in very good agreement with the X-ray data. The distribution of bond distances reveals the presence of a strong Mills—Nixon effect which has been questioned many times in similar systems. The origin of the highly pronounced Mills—Nixon effect is analyzed. It is found that it arises due to concerted and synergistic action of σ- and Π-electrons which leads to Mills—Nixon type of bond fixation.

Prediction of enzyme binding: human thrombin inhibition study by quantum chemical and artificial intelligence methods based on X-ray structures.

Thrombin is a serine protease which plays important roles in the human body, the key one being the control of thrombus formation. The inhibition of thrombin has become a target for new antithrombotics. The aim of our work was to (i) construct a model which would enable us to predict Ki values for the binding of an inhibitor into the active site of thrombin based on a database of known X-ray structures of inhibitor-enzyme complexes and (ii) to identify the structural and electrostatic characteristics of inhibitor molecules crucially important to their effective binding. To retain as much of the 3D structural information of the bound inhibitor as possible, we implemented the quantum mechanical/molecular mechanical (QM/MM) procedure for calculating the molecular electrostatic potential (MEP) at the van der Waals surfaces of atoms in the proteins active site. The inhibitor was treated quantum mechanically, while the rest of the complex was treated by classical means. The obtained MEP values served as inputs into the counter-propagation artificial neural network (CP-ANN), and a genetic algorithm was subsequently used to search for the combination of atoms that predominantly influences the binding. The constructed CP-ANN model yielded Ki values predictions with a correlation coefficient of 0.96, with Ki values extended over 7 orders of magnitude. Our approach also shows the relative importance of the various amino acid residues present in the active site of the enzyme for inhibitor binding. The list of residues selected by our automatic procedure is in good correlation with the current consensus regarding the importance of certain crucial residues in thrombins active site.