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1.
Artigo em Inglês | MEDLINE | ID: mdl-31586414

RESUMO

BACKGROUND: Darunavir/cobicistat can be used as mono, dual, triple or more than triple therapy. OBJECTIVES: To assess factors associated with the number of drugs in darunavir/cobicistat regimens. METHODS: A nationwide retrospective cohort study of consecutive HIV-infected patients initiating darunavir/cobicistat in Spain from July 2015 to May 2017. Baseline characteristics, efficacy and safety at 48 weeks were compared according to the number of drugs used. RESULTS: There were 761 patients (75% men, 98% were antiretroviral-experienced, 32% had prior AIDS, 84% had HIV RNA <50 copies/mL and 88% had ≥200 CD4 cells/mm3) who initiated darunavir/cobicistat as mono (n=308, 40%), dual (n=173, 23%), triple (n=253, 33%) or four-drug (n=27, 4%) therapy. Relative to monotherapy, triple therapy was more common in men aged <50 years, with prior AIDS and darunavir plus ritonavir use, and with CD4 cells <200/mm3 and with detectable viral load at initiation of darunavir/cobicistat; dual therapy was more common with previous intravenous drug use, detectable viral load at initiation of darunavir/cobicistat and no prior darunavir plus ritonavir; and four-drug therapy was more common with prior AIDS and detectable viral load at initiation of darunavir/cobicistat. Monotherapy and dual therapy showed a trend to better virological responses than triple therapy. CD4 responses and adverse effects did not differ among regimens. DISCUSSION: Darunavir/cobicistat use in Spain has been tailored according to clinical characteristics of HIV-infected patients. Monotherapy and dual therapy have been common and preferentially addressed to older patients with a better HIV status, suggesting that health issues other than HIV infection may have been strong determinants of its prescription.

2.
Lancet HIV ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31635990
3.
J Antimicrob Chemother ; 74(9): 2742-2751, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31269208

RESUMO

BACKGROUND: Dual therapy combining integrase inhibitors and NNRTIs represents a promising regimen in ageing HIV-infected individuals with long exposure to nucleoside analogues and PIs. METHODS: The ANRS 163 ETRAL trial (NCT02212379) was a 96 week, multicentre, single-arm study evaluating the efficacy and safety of raltegravir (400 mg twice daily)/etravirine (200 mg twice daily) in individuals >45 years, on a PI-containing regimen who were integrase inhibitor and etravirine naive. The primary endpoint was the proportion of participants with virological success, defined by the absence of virological failure up to week 48. Main secondary outcomes included evolution of metabolic parameters, CD4/CD8 count, bone mineral density and inflammatory markers. The study was designed to show an efficacy >90%, assuming a success rate ≥95%, with a power of 80% and a 5% type-1 error. RESULTS: One hundred and sixty-five participants (median age 52 years, duration of ART 16.9 years, viral suppression 6.9 years and CD4 count 700 cells/mm3) were enrolled. By ITT analysis, viral suppression was maintained in 99.4% of participants (95% CI = 95.6%-99.9%) at week 48 and 98.7% (95% CI = 95.0%-99.7%) at week 96. Two virological failures occurred (week 24 and week 64) without emergence of integrase inhibitor resistance. Eight participants discontinued raltegravir/etravirine for adverse events, leading to a strategy success rate of 95.1% (95% CI = 90.5%-97.5%) at week 48 and 92.7% (95% CI = 87.5%-95.8%) at week 96. Over 96 weeks, lipid fractions improved (P < 0.001), CD4/CD8 ratio increased, IFNγ-induced protein 10 (IP-10) decreased (-8.1%), soluble CD14 decreased (-27%, P < 0.001) bone mineral density improved and BMI increased. CONCLUSIONS: Raltegravir plus etravirine dual therapy demonstrated durable efficacy in virologically suppressed ageing patients.

4.
J Bone Miner Res ; 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31361922

RESUMO

Zoledronic acid (ZOL) 5 mg annually was more effective than tenofovir disoproxil fumarate (TDF) switching at increasing bone mineral density (BMD) over 24 months in HIV-infected, osteopenic adults. To determine whether the effects of ZOL would persist without further infusions, we compared changes in left hip and spine BMD over 36 months in participants randomized to ZOL 5 mg at baseline and month 12 (and to continue TDF) or to switch TDF (without receiving ZOL). We also compared changes in the plasma bone turnover markers (BTMs) C-terminal telopeptide of type 1 collagen (CTX; bone resorption), and procollagen type 1 N propeptide (P1NP; bone formation) and determined whether CTX and P1NP changes at month 3 predicted BMD changes at month 36. Changes were compared in the per-protocol populations, which included 32 (74%) of 43 participants randomized to ZOL and 37 (88%) of 42 participants who switched TDF. Despite not receiving ZOL after month 12, mean hip and spine BMD change from baseline were stable and remained greater with ZOL at month 36 than with TDF switching (spine: 7.5% versus 2.7%, mean difference 4.7%, p < 0.001; hip: 5.5% versus 1.5%, mean difference 4.0%, p < 0.001). CTX and P1NP levels declined in both groups but significantly more with ZOL. Only percent changes in P1NP at month 3 correlated inversely with BMD changes at month 36 (spine: rho = -0.442, p < 0.001; hip: rho = -0.373, p = 0.002). Two infusions of ZOL (in the presence of ongoing TDF) yielded sustained BMD increases through month 36 that remained greater than with TDF switching. © 2019 American Society for Bone and Mineral Research.

5.
AIDS ; 33(12): 1891-1896, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31335805

RESUMO

BACKGROUND: There is an increasing interest in two-drug regimens. We hypothesized that maintenance therapy with raltegravir and lamivudine would keep HIV-1 suppressed and be well tolerated. METHODS: Virally suppressed HIV-1-infected adults without previous viral failures or known resistance mutations to integrase inhibitors or 3TC/FTC or chronic hepatitis B were randomized 2 : 1 to switch to fixed-dose combination 150 mg lamivudine/300 mg raltegravir twice daily or to continue therapy. Primary outcome was the proportion of patients free of therapeutic failure (defined as viral failure, change in treatment for any reason, consent withdrawal, loss to follow-up or death) at week 24. Secondary outcomes were changes in laboratory, body composition, sleep quality, adherence, and adverse effects. RESULTS: There were 75 patients included: men 78%; median age 50 years; median CD4 622/µl. At week 24, 7 (9%) patients had therapeutic failure: raltegravir and lamivudine 2 (4%) vs. control 5 (20%). The difference in proportions of therapeutic failures raltegravir and lamivudine minus control was -0.159 (95% confidence interval: -0.353 to -0.012). There was a trend to more weight gain with raltegravir and lamivudine, but no significant changes in other secondary outcomes. Sixty-four percent of patients in each arm had at least one adverse effect. Two (6%) patients in control arm and 4 (7%) patients in raltegravir and lamivudine arm had severe adverse effects. CONCLUSION: This pilot study suggests that switching to raltegravir along with lamivudine in patients with viral suppression maintains efficacy and is well tolerated. A larger study of longer duration is required to confirm these findings.

6.
Proc Natl Acad Sci U S A ; 116(28): 13964-13969, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31243147

RESUMO

Carboxylases are biocatalysts that capture and convert carbon dioxide (CO2) under mild conditions and atmospheric concentrations at a scale of more than 400 Gt annually. However, how these enzymes bind and control the gaseous CO2 molecule during catalysis is only poorly understood. One of the most efficient classes of carboxylating enzymes are enoyl-CoA carboxylases/reductases (Ecrs), which outcompete the plant enzyme RuBisCO in catalytic efficiency and fidelity by more than an order of magnitude. Here we investigated the interactions of CO2 within the active site of Ecr from Kitasatospora setae Combining experimental biochemistry, protein crystallography, and advanced computer simulations we show that 4 amino acids, N81, F170, E171, and H365, are required to create a highly efficient CO2-fixing enzyme. Together, these 4 residues anchor and position the CO2 molecule for the attack by a reactive enolate created during the catalytic cycle. Notably, a highly ordered water molecule plays an important role in an active site that is otherwise carefully shielded from water, which is detrimental to CO2 fixation. Altogether, our study reveals unprecedented molecular details of selective CO2 binding and C-C-bond formation during the catalytic cycle of nature's most efficient CO2-fixing enzyme. This knowledge provides the basis for the future development of catalytic frameworks for the capture and conversion of CO2 in biology and chemistry.

7.
J Am Chem Soc ; 141(25): 9778-9782, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31188584

RESUMO

Developing new carbon dioxide (CO2) fixing enzymes is a prerequisite to create new biocatalysts for diverse applications in chemistry, biotechnology and synthetic biology. Here we used bioinformatics to identify a "sleeping carboxylase function" in the superfamily of medium-chain dehydrogenases/reductases (MDR), i.e. enzymes that possess a low carboxylation side activity next to their original enzyme reaction. We show that propionyl-CoA synthase from Erythrobacter sp. NAP1, as well as an acrylyl-CoA reductase from Nitrosopumilus maritimus possess carboxylation yields of 3 ± 1 and 4.5 ± 0.9%. We use rational design to engineer these enzymes further into carboxylases by increasing interactions of the proteins with CO2 and suppressing diffusion of water to the active site. The engineered carboxylases show improved CO2-binding and kinetic parameters comparable to naturally existing CO2-fixing enzymes. Our results provide a strategy to develop novel CO2-fixing enzymes and shed light on the emergence of natural carboxylases during evolution.

8.
Ther Innov Regul Sci ; : 2168479019841314, 2019 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-31079486

RESUMO

Notwithstanding successful harmonization efforts, the global regulatory framework governing product safety is complex and continually evolving, as evidenced by additional regional guidance and regulations. In this regulatory review, we provide an overview from both global and regional perspectives. A historical perspective, with a focus on recent developments, enables identification of important long-term trends, such as a shift from single-case medical review of serious adverse events to an interdisciplinary evaluation of aggregate data for the purpose of judging product causality and informing benefit-risk assessments. We will show how these trends lead to opportunities for closer interdisciplinary collaboration, for bridging the gap between pre- and postmarketing surveillance, and for a more proactive determination of patient populations with a positive benefit-risk profile for product use. We will conclude by pointing to ongoing and future work that seeks to provide specific solutions for ongoing aggregate safety evaluation.

9.
PLoS One ; 14(5): e0216712, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31120908

RESUMO

CONTEXT: Classical antiretroviral agents may acutely impact on metabolic, mitochondrial, renal and hepatic function in HIV-infected and uninfected persons. Fusion and integrase inhibitors are supposed to be safer, but have been scarcely investigated. To avoid any interference with HIV or other antiretrovirals, we assessed markers of these toxicities in healthy adult volunteers treated with Enfuvirtide (T20) or Raltegravir (RAL). METHODS: Twenty-six healthy participants were randomized to T20/90mg vs. placebo (n = 12) or RAL/400mg vs. placebo (n = 14) every 12h in two 7-day periods separated by a 4-week washout period. Major end-points were changes in lipid profile (total cholesterol, high-density-lipoprotein (HDL)-cholesterol, low-density-lipoprotein (LDL)-cholesterol, triglycerides), insulin resistance (glucose) and mitochondrial toxicity (mitochondrial DNA content-mtDNA-in peripheral blood mononuclear cells). Renal and hepatic toxicity (creatinine, alanine transaminase (AST), alanine aminotransferase (ALT), bilirubin and total plasma proteins) and overall safety were also analysed. Effect of period, treatment, and basal measures were evaluated for each end-point. RESULTS: Neither T20-administration nor RAL-administration yielded to any statistic significant change in the markers of metabolic, mitochondrial, renal or hepatic toxicity assessed. No symptoms indicative of drug toxicity were neither found in any subject. CONCLUSIONS: In absence of HIV infection, or concomitant treatment, short-term exposure to T20 or RAL in healthy adult volunteers did not lead to any indicative changes in toxicity markers thus presuming the safe profile of both drugs.

10.
AIDS ; 33(6): 965-972, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30946150

RESUMO

BACKGROUND: Atripla dose reduction decreases subclinical toxicity and maintains viral suppression in HIV+ individuals but the virological efficacy and immunological safety of this strategy needs to be further confirmed. METHODS: Virologically suppressed HIV-infected adults on Atripla once-daily were randomized 1 : 1 to reduce therapy to 3 days a week (3W, n = 30) or to maintain it unchanged (once-daily, n = 31). HIV-1 reservoir (total and integrated HIV-1 DNA in CD4 cells) and immunological cell activation (CD38 and HLA-DR), senescence (CD57 and CD28), apoptosis (annexinV) as well as T-naive, effector memory (TEM) (CCR7, CD45RA) and stem cell memory (TSCM) (CD954 and CD27) populations were measured at baseline, 24 and 48 weeks. RESULTS: No differences on activation, senescence or apoptosis of both CD4 and CD8 T cells were observed on follow-up. Nave CD4 T-cell proportion showed a significant decrease in the 3W group (mean ±â€ŠSD): 24.6 ±â€Š13.7 vs. 20.5 ±â€Š12.9 (P = 0.002). No differences in both plasma viral load and HIV reservoir were detected on follow-up. CD4 TSCM levels at 48 weeks correlated with basal integrated HIV-1 DNA in the 3W group but not in the once-daily group. A post hoc analysis of data prior to the study entry revealed a higher viral load zenith and a trend to lower CD4 nadir in 3W vs. once-daily group. CONCLUSION: No significant immunological or viral changes were induced in the 3W group confirming the virological efficacy and immunogical safety of this strategy. In-depth virological and immunological analyses are useful in providing additional information in antiretroviral switching studies (Clinical Trials.gov: NCT01778413).

11.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 37(3): 151-159, mar. 2019. graf, tab
Artigo em Inglês | IBECS | ID: ibc-181298

RESUMO

Background: The GESIDA/National AIDS Plan expert panel recommended preferred regimens (PR), alternative regimens (AR) and other regimens (OR) for antiretroviral treatment (ART) as initial therapy in HIV-infected patients for 2018. The objective of this study was to evaluate the costs and the efficiency of initiating treatment with PR and AR. Methods: Economic assessment of costs and efficiency (cost-effectiveness) based on decision tree analyses. Effectiveness was defined as the probability of reporting a viral load <50 copies/mL at week 48, in an intention-to-treat analysis. Cost of initiating treatment with an ART regimen was defined as the costs of ART and its consequences (adverse effects, changes of ART regimen, and drug-resistance studies) over the first 48 weeks. The payer perspective (National Health System) was applied considering only differential direct costs: ART (official prices), management of adverse effects, studies of resistance, and HLA B*5701 testing. The setting was Spain and the costs correspond to those of 2018. A deterministic sensitivity analysis was conducted, building three scenarios for each regimen: base case, most favourable and least favourable. Results: In the base-case scenario, the cost of initiating treatment ranges from 6788 euros for TAF/FTC/RPV (AR) to 10,649 euros for TAF/FTC + RAL (PR). The effectiveness varies from 0.82 for TAF/FTC + DRV/r (AR) to 0.91 for TAF/FTC+DTG (PR). The efficiency, in terms of cost-effectiveness, ranges from 7814 to 12,412 euros per responder at 48 weeks, for ABC/3TC/DTG (PR) and TAF/FTC + RAL (PR), respectively. Conclusion: Considering ART official prices, the most efficient regimen was ABC/3TC/DTG (PR), followed by TAF/FTC/RPV (AR) and TAF/FTC/EVG/COBI (AR)


Introducción El panel de expertos de GESIDA/Plan Nacional del Sida ha recomendado pautas preferentes (PP), pautas alternativas (PA) y otras pautas (OP) para el tratamiento antirretroviral (TAR) como terapia de inicio en pacientes infectados por VIH para 2018. El objetivo de este estudio es evaluar los costes y la eficiencia de iniciar tratamiento con PP y PA. Métodos: Evaluación económica de costes y eficiencia (coste/eficacia) mediante construcción de árboles de decisión. Se definió eficacia como la probabilidad de tener carga viral <50 copias/ml en la semana 48 en análisis por intención de tratar. Se definió coste de iniciar tratamiento con una pauta como los costes del TAR y de todas sus consecuencias (efectos adversos, cambios de pauta y estudio de resistencias) que se producen en las siguientes 48 semanas. Se utilizó la perspectiva del Sistema Nacional de Salud, considerando solo costes directos diferenciales: TAR (a precio oficial), manejo de efectos adversos, estudios de resistencias y determinación de HLA-B*5701. El ámbito es España, con costes de 2018. Se realizó un análisis de sensibilidad determinista construyendo 3 escenarios para cada pauta: basal, más favorable y más desfavorable. Resultados: En el escenario basal, los costes de iniciar tratamiento oscilaron entre 6.788 para TAF/FTC/RPV (PA) y 10.649 para TAF/FTC+RAL (PP). La eficacia osciló entre 0,82 para TAF/FTC+DRV/r (PA) y 0,91 para TAF/FTC+DTG (PP). La eficiencia, en términos de coste/eficacia, osciló entre 7.814 y 12.412 por respondedor a las 48 semanas, para ABC/3TC/DTG (PP) y TAF/FTC+RAL (PP), respectivamente. Conclusión: Considerando el precio oficial del TAR, la pauta más eficiente fue ABC/3TC/DTG (PP), seguida de TAF/FTC/RPV (PA) y AF/FTC/EVG/COBI (PA)


Assuntos
Humanos , Adulto , Antirretrovirais/economia , Antirretrovirais/uso terapêutico , Análise Custo-Benefício , HIV , Fármacos Anti-HIV/uso terapêutico
12.
Proteins ; 87(6): 467-477, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30714651

RESUMO

Thioredoxin is a protein that has been used as model system by various computational methods to predict the pKa of aspartate residue Asp26 which is 3.5 units higher than a solvent exposed one (eg, Asp20). Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation, the Gibbs free energy of proton transfer between Asp26 and Asp20, which is fully solvated in a loop region of the protein, is calculated with the Amber99sb force field in alchemical transformations. The varying polarization of the two residues in different molecular environments and protonation states is described by Hirshfeld-I (HI) atomic charges obtained from the averaged polarized electron density. Our results show that the Gibbs free energy of proton transfer is dependent on the protein conformation, the proper sampling of the neighboring Lys57 residue orientations and on water molecules entering the hydrophobic cavity upon deprotonating Asp26. The inclusion of the polarization of both aspartate residues in the free energy cycle by HI atomic charges corrects the results from the non-polarizable force field and reproduces the experimental ΔpKa value of Asp26.

13.
J Comput Chem ; 40(13): 1401-1413, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30770583

RESUMO

Carboxylation reactions represent a very special class of chemical reactions that is characterized by the presence of a carbon dioxide (CO2 ) molecule as reactive species within its global chemical equation. These reactions work as fundamental gear to accomplish the CO2 fixation and thus to build up more complex molecules through different technological and biochemical processes. In this context, a correct description of the CO2 electronic structure turns out to be crucial to study the chemical and electronic properties associated with this kind of reactions. Here, a systematic study of CO2 electronic structure and its contribution to different carboxylation reaction electronic energies has been carried out by means of several high-level ab initio post-Hartree Fock (post-HF) and density functional theory (DFT) calculations for a set of biochemistry and inorganic systems. We have found that for a correct description of the CO2 electronic correlation energy it is necessary to include post-CCSD(T) contributions (beyond the gold standard). These high-order excitations are required to properly describe the interactions of the four π-electrons associated with the two degenerated π-molecular orbitals of the CO2 molecule. Likewise, our results show that in some reactions it is possible to obtain accurate reaction electronic energy values with computationally less demanding methods when the error in the electronic correlation energy compensates between reactants and products. Furthermore, the provided post-HF reference values allowed to validating different DFT exchange-correlation functionals combined with different basis sets for chemical reactions that are relevant in biochemical CO2 fixing enzymes. © 2019 Wiley Periodicals, Inc.

17.
Cell Rep ; 24(13): 3513-3527.e7, 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30257212

RESUMO

BRCA1 functions in homologous recombination (HR) both up- and downstream of DNA end resection. However, in cells with 53BP1 gene knockout (KO), BRCA1 is dispensable for the initiation of resection, but whether BRCA1 activity is entirely redundant after end resection is unclear. Here, we found that 53bp1 KO rescued the embryonic viability of a Brca1ΔC/ΔC mouse model that harbors a stop codon in the coiled-coil domain. However, Brca1ΔC/ΔC;53bp1-/- mice were susceptible to tumor formation, lacked Rad51 foci, and were sensitive to PARP inhibitor (PARPi) treatment, indicative of suboptimal HR. Furthermore, BRCA1 mutant cancer cell lines were dependent on truncated BRCA1 proteins that retained the ability to interact with PALB2 for 53BP1 KO induced RAD51 foci and PARPi resistance. Our data suggest that the overall efficiency of 53BP1 loss of function induced HR may be BRCA1 mutation dependent. In the setting of 53BP1 KO, hypomorphic BRCA1 proteins are active downstream of end resection, promoting RAD51 loading and PARPi resistance.

18.
J Lipid Res ; 59(11): 2108-2115, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30213800

RESUMO

Cholesterol efflux (CE) capacity has been inversely associated with atherosclerosis and may provide an insight on inflammation occurring in human immunodeficiency virus (HIV) individuals. We address this by studying CE in HIV patients at different stages of HIV disease progression. In this cross-sectional study, CE from ApoB-depleted plasma, lipids levels, viral load (VL), CD4+/CD8+ T-cells, high-sensitive C-reactive protein (hsCRP), and lipoprotein (a) were evaluated in untreated HIV-infected patients (UHIVs; n = 43), elite controllers (ECs; n = 8), HIV-exposed seronegative individuals (HESNs; n = 32), and healthy controls (HCs; n = 14). Among UHIVs, those with CD4+ <500 cells/mm3 presented the lowest significant CE, HDL cholesterol (HDL-C), and ApoAI levels. ECs showed similar HDL-C, ApoAI, and CE compared with HCs. Among UHIVs, CE positively correlated with CD4+ T-cell counts (Beta: 1.05; 95% CI: 1.02; 1.07), and for VL higher than 3.8 log, CE was inversely associated with VL (Beta: 0.70; 95% CI: 0.51; 0.95). Remarkably, HESNs presented higher CE (0.78 ± 0.14) than UHIVs (0.65 ± 0.17; P = 0.0005), but lower than HCs (0.90 ± 0.13; P = 0.009). hsCRP levels were highest in the UHIV group (0.45 ± 0.49). CE was sensitive to HIV disease progression. Low CE in HIV patients was associated with lower CD4+ T-cells and higher VL and hsCRP. CE was also lower in HESNs compared with HCs. Our results suggest that immune status secondary to HIV progression and exposure influence plasma HDL-CE capacity.

19.
J Phys Chem B ; 122(38): 8861-8871, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30157632

RESUMO

Catechol- O-methyltransferase is an enzyme that catalyzes the methylation reaction of dopamine by S-adenosylmethionine, increasing the reaction rate by almost 16 orders of magnitude compared to the reaction in aqueous solution. Here, we combine the recently introduced adaptive string method and the mean reaction force method, in combination with the structural and electronic descriptors to characterize the reaction mechanism. The catalytic effect of the enzyme is addressed by the comparison of the reaction in the human wild-type enzyme, in the less effective Y68A mutant, and in aqueous solution. The influence of these different environments at different stages of the chemical process and the significance of the key collective variables describing the reaction were quantified. Our results show that the native enzyme limits the access of water molecules to the active site, enhancing the interaction between the reactants and providing a more favorable electrostatic environment to assist the SN2 methyl transfer reaction.

20.
J Chem Inf Model ; 58(9): 1779-1797, 2018 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-30125107

RESUMO

Computer simulations of biomolecular systems often use force fields, which are combinations of simple empirical atom-based functions to describe the molecular interactions. Even though polarizable force fields give a more detailed description of intermolecular interactions, nonpolarizable force fields, developed several decades ago, are often still preferred because of their reduced computation cost. Electrostatic interactions play a major role in biomolecular systems and are therein described by atomic point charges. In this work, we address the performance of different atomic charges to reproduce experimental hydration free energies in the FreeSolv database in combination with the GAFF force field. Atomic charges were calculated by two atoms-in-molecules approaches, Hirshfeld-I and Minimal Basis Iterative Stockholder (MBIS). To account for polarization effects, the charges were derived from the solute's electron density computed with an implicit solvent model, and the energy required to polarize the solute was added to the free energy cycle. The calculated hydration free energies were analyzed with an error model, revealing systematic errors associated with specific functional groups or chemical elements. The best agreement with the experimental data is observed for the AM1-BCC and the MBIS atomic charge methods. The latter includes the solvent polarization and presents a root-mean-square error of 2.0 kcal mol-1 for the 613 organic molecules studied. The largest deviation was observed for phosphorus-containing molecules and the molecules with amide, ester and amine functional groups.

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